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Type I interferons are a class of potent and tightly regulated cytokines important for antiviral and anti-tumoural innate and adaptive immunity. Dysregulated production can have serious neurologic consequences as exemplified in a family of rare diseases called type I interferonopathies. Interferonopathies represent a group of genetically determined conditions characterised by upregulated type I interferon production causing a spectrum of neuroinflammatory and systemic manifestations. This chapter delves into the historical discovery of type I interferons, their role in innate immunity, and the subsequent identification of interferonopathies placing emphasis on the mechanisms of neurologic dysfunction that often dominate the clinical picture. The insights gained from studying these rare diseases offer valuable lessons for neurodegenerative and neuropsychiatric conditions which demonstrate considerable overlap with interferonopathies, underscoring the broader significance of type I interferons in more common neurologic diseases. Relevant therapeutic strategies targeting this pathway are discussed, emphasising the need for brain-penetrant approaches.
Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
AC Immune SA, EPFL Innovation Park, Lausanne, Switzerland
*Address all correspondence to: alessio.mylonas@epfl.ch
1. Introduction
Type I interferonopathies, or simply interferonopathies, are a family of rare autoinflammatory diseases typified by overt sustained activation of type I interferon signalling. In their most characteristic appearance, interferonopathies are a form of neuroinflammatory disease with a genetic origin. In recent years, type I interferons have been implicated in an increasing number of neurologic diseases, raising the question of whether a better understanding of interferonopathies can enhance our knowledge of neurodegeneration mechanisms.
In this chapter, interferonopathies and the type I interferon pathway are introduced, and they are contextualised with our current knowledge of the biology and the underlying immunologic mechanisms. This is then examined in relation to the continuously expanding spectrum of neuropsychiatric diseases induced by interferon dysfunction. While interferonopathies are rare monogenic diseases, dysregulation of the type I interferon pathway has important implications for more common polygenic diseases. Our understanding of this pathway, of these rare interferonopathies, and of the more common interferon dysfunction diseases that they have parallels with, has allowed for great advances in the development of interferon as a therapeutic target with potentially great future clinical implications.
1.1 Historical perspective
Type I interferonopathies are a recent concept encompassing a diverse family of diseases. The term was first introduced by Yanick Crow in 2011 who proposed a unifying notion for several Mendelian diseases that share clinical and molecular features and, importantly, which involve type I interferon dysregulation [1]. Yet the history of type I interferonopathies dates all the way back to the early 1980s, when the deleterious effects of interferons were first observed and hypothesised.
The discovery of type I interferons is a fascinating story of scientific serendipity and perseverance. Interferons have been studied since the mid-1950s, when famous Alick Isaacs and Jean Lindenmann reported the discovery of a soluble factor that could interfere with the replication of influenza virus which they named “interferon” [2, 3]. Initially, the two microbiologists were studying the influenza virus and the resulting cytopathic activity in chick cells and remarked that some cells were more resistant to the infection and importantly that this resistance could be transferred. While fraught with resistance and scepticism from the research community, and hampered by technological limitations, this discovery paved the way for unprecedented therapeutic advances. Years later, it was discovered that many different interferons exist, with broadly overlapping induction mechanisms, functions, and biological effects. Importantly, it was discovered that exogenous delivery could be leveraged for therapeutic benefit in patients.
The first human use of interferons occurred in 1973. A non-purified interferon preparation was delivered intranasally to healthy volunteers later exposed to rhinovirus, demonstrating antiviral immunity in humans for the first time [4]. Aside from their antiviral function, anti-tumour activities were described [5] paving the way for the first antitumour use in humans [6] and the first approval of recombinant IFNα therapy for hairy cell leukaemia in 1986. Later, immunoregulatory effects were also unintentionally discovered in multiple sclerosis (MS), an autoimmune disease, reasoned to be triggered by viral infections [7]. Today, type I interferons, the very same subtype that Isaacs and Lindenmann had first discovered, are used in the treatment of many viral infections, cancers, and even multiple sclerosis. They have also become essential for our understanding of the molecular and cellular basis of innate immunity and host-pathogen interactions. In parallel, as their use increased in the clinics, it very quickly became clear that they also induced psychocognitive effects [8, 9, 10], and that they may also induce de novo autoimmunity [11].
In 1978, Ion Gresser, a pioneer of research on the antiviral and antitumoral effects of interferons, demonstrated the counterintuitive benefits of IFNα-neutralising immunoglobulins during acute disease caused by infection [12]. This important observation was the first of many that would contrast the beneficial and detrimental of effects of type I interferons [13] and set the tone for the field for years to come. In many respects, this finding also foretold the great medical advances that would later be anti-cytokine therapies, first with anti-TNF in 1992 [14] and today with the first approved anti-interferon signalling therapies [15].
Around the same time, Jean Aicardi and Françoise Goutières reported eight children with severe early onset encephalopathy, characterised by calcification of the basal ganglia, white matter abnormalities, and calcification of the basal ganglia [16], but the underlying pathomechanism remained unclear. Fuelled by great interest in viral immunity, and the effects of interferons, Aicardi and colleagues investigated the cerebrospinal fluid and sera of these patients, and found that they had high levels of IFNα in both, yet could not attribute a viral aetiology to this [17]. It was many years later that Yanick Crow, Thomas Lindahl, and colleagues attributed to the Aicardi-Goutieres syndrome (AGS) to loss-of-function mutations of the TREX1 gene encoding a DNA exonuclease [18] and of the RNASEH2A, RNASEH2B, and RNASEH2C genes encoding subunits of the RNA endonuclease RNASEH2 [19]. AGS would later be recognised as the archetypical type I interferonopathy, and one of many which are still being discovered (Figure 1).
Figure 1.
Chronological overview of type I interferon-related discoveries. From the discovery of the virus-induced “interference” factors in 1957, type I interferons have been centre-stage for therapeutic development, both as exogenous administration, as disease biomarker, and ultimately as anti-cytokine therapy. From the first in human use of interferons first as an antiviral in 1973 and later for the treatment of MS and tumours in 1981, to the first approval of recombinant IFNα in 1986, type I interferons have provided numerous clinical benefits for patients across different disease areas. In the space of 16 years, interferons had gone from discovery to clinical use, a remarkable achievement for the time. Concurrently, reports of psychocognitive side effects were starting to appear from 1980 onwards, a testament to the immediacy of the effect in the CNS of these highly bioactive cytokines. It quickly became apparent that interferon therapy could lead to numerous other side effects such as SLE, and its involvement in autoinflammatory and autoimmune diseases was thereby discovered. The first description of Aicardi-Goutières Syndrome 1984, prior to the genomics revolution of the 2000s, would lead to the discovery of a new and expanding disease family called “interferonopathies”. Despite the first preclinical evidence of the benefits of anti-interferon biologic use in 1978, it would take 43 years to the first approval of an anti-interferon signalling therapy, a full 28 years after the first anti-cytokine biologic therapy. The list of potential indications that could benefit from targeted inhibition of the type I interferon pathway is still being determined with ongoing clinical trials and case studies across different autoinflammatory and autoimmune diseases.
1.2 Definition and classification of interferonopathies
Few cohort studies have so far been published, and many aspects are derived from case reports. Although type I interferonopathies are defined by similar underlying mechanisms, they are a family of diseases with distinct genetic alterations and a classification has been formulated based on clinical and genetic features (Table 1). Broadly, these can be sub-classified as monogenic interferonopathies and non-monogenic type I interferon dysfunction diseases, forming classical interferonopathies, brain vasculopathies, and one autoimmune disease.
Interferonopathies are a monogenic family of diseases caused by mutations in genes involved in the recognition, production, or regulation of type I interferons. These mutations lead to nucleic acid or metabolite accumulation, activating cytosolic nucleic acid sensors. These sensors then induce the production and secretion of type I interferons, which bind to their receptors on the cell surface and initiate a signalling cascade that involves the phosphorylation and nuclear translocation of transcription factors. They thereby activate expression of hundreds of interferon-stimulated genes (ISGs), which mediate the antiviral, immunomodulatory, and inflammatory effects of type I interferons.
Interferonopathies can be classified into six main diseases, based on the clinical presentation and the genetic defect: (1) Aicardi-Goutières syndrome (AGS), (2) USP18 and ISG15 loss-of-function diseases, (3) spondyloenchondrodysplasia (SPENCD), (4) proteasome-associated autoinflammatory syndromes (PRAAS), (5) STING-associated vasculopathy with onset in infancy (SAVI), and (6) Singleton-Merten syndrome (SMS).
AGS is the most common among type I interferonopathies and is characterised by early-onset encephalopathy, calcification of the basal ganglia, leukodystrophy, skin lesions, and systemic inflammation. It is caused by mutations in genes encoding nucleases, such as TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR1, or genes involved in nucleic acid metabolism, such as RNASEH2, IFIH1, and ADAR2. These mutations impair the degradation or editing of endogenous nucleic acids, leading to the accumulation of self-DNA or RNA, which activate the cGAS-STING or RIG-I-MDA5 pathways, respectively. Gain-of-function mutations in STAT2 have also been identified [20, 21, 22, 23], bypassing nucleic acid metabolism steps and highlighting the complexity of AGS. USP18 and ISG15 loss-of-function diseases share important similarities and display neuropathology similar to AGS. SPENCD and PRAAS are less well studied, and the mechanism by which type I interferons are induced is undefined, though patients also display basal ganglia calcifications.
Among the typically non encephalitogenic type I interferonopathies, SAVI is perhaps the better studied. It is caused by gain-of-function mutations in STING1 (previously TMEM173), encoding the stimulator of interferon genes (STING) protein. STING is a key adaptor protein that activates type I interferon signalling in response to cytosolic DNA. It is diagnosed by genetic testing and by blood measurements of interferon response. Unlike AGS, systemic, rather than principally CNS-centred, symptoms are more pronounced, and often quite disparate. Early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease have been described, with rare cases of accompanying alopecia [24]. The skin lesions typically affect the fingers, toes, ears, and nose and can lead to ulceration, necrosis, and sometimes amputation. The lung disease manifests as progressive fibrosis, respiratory failure, and pulmonary hypertension. What is surprising is that, often these symptoms can occur without simultaneous involvement of both skin and lungs. Yet, upon imaging, occasionally intracerebral calcifications are also observed and can aid diagnosis. Only a handful of cases have been reported so far; thus, many questions remain as to the differential clinical signs. SMS, while also a classical interferonopathy, presents with a yet different array of symptoms, including skin inflammation, calcifications of the aorta, and progressive osteoporosis. Neurologic symptoms have also been reported though they are not thought as the main clinical sign.
With more attentive clinical investigations, additional rare type I interferonopathies are being discovered. It is important to note that not all of them present with overt neurological signs and often certain subtypes will include patients with severe psychocognitive disease while others display only systemic signs of disease. The underlying cause for this is largely unknown. Throughout the rest of the chapter, special emphasis will be put on encephalopathic diseases.
1.3 Overview of type I interferon pathway
Being a complex and tightly regulated network of molecular interactions, this pathway mediates cellular responses to infections, as well as endogenous nucleic acids when recognised as danger signals. The pathway can be divided into three overarching stages: (1) sensing, (2) signalling, and (3) feedback regulation (Figure 2).
Figure 2.
Type I interferon signalling regulation and pathway. Simplified summary of triggering molecules, associated sensors, type I interferons produced, receptor-mediated signalling, and generic interferon-responses.
Sensing refers to the recognition of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and cGAS-STING. These receptors are expressed in different cellular compartments, such as the plasma membrane (TLR1, -2, -4, -5, -6), endosomes (TLR3, -7, -8, -9), cytosol (MDA-5, RIG-I, cGAS-STING, ZBP1, etc.), or nucleus (IFI16, hnRNPA2B1, cGAS in some contexts, etc.), and can detect different types of nucleic acids, such as viral or bacterial DNA or RNA, or self-DNA or RNA. Upon ligand binding, these receptors activate downstream signalling pathways that converge on the activation of interferon regulatory transcription factor 3 (IRF3) and 7 (IRF7), the master transcription factors of type I interferons [25].
Signalling initiates when binding to its cognate receptor is achieved, triggering the induction of downstream pathways and amplification of type I interferon production. IRF3 and IRF7 translocate to the nucleus and bind to the interferon-stimulated response elements (ISREs) in the promoters of type I interferon genes, such as IFNA1, IFNA2, and IFNB1, and induce their transcription, translation, and secretion. They then bind to their receptor, the interferon α/β receptor (IFNAR) formed of two chains: IFNAR1 and IFNAR2. This signalling can take place on the same or neighbouring cells and activate the Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway, which involves the phosphorylation and nuclear translocation of STAT1 and -2. These STATs form a complex with IRF9, called ISGF3, which binds to the ISREs in the promoters of ISGs, such as MX1, OAS1, and ISG15, and induce their transcription and expression. ISGs mediate the antiviral, immunomodulatory, and inflammatory effects of type I interferons. Other non-canonical pathways independent of JAK-STAT are also known to be activated in a cell- or context-specific manner, and signalling is mediated through PI3K-mTOR, NF-κB, and MAPK and can have broad outcomes [26, 27, 28].
Feedback regulation is initiated simultaneously following signalling, triggering both positive and negative modulation mechanisms for the pathway. Positive feedback loops involve the induction of IRF7, which enhances the expression of more type I interferons and ISGs, creating a feedforward loop that amplifies the response. Negative feedback loops involve the induction of suppressors of cytokine signalling (SOCS), protein inhibitors of activated STATs (PIAS), and ubiquitin-specific proteases (USPs), which inhibit the JAK-STAT pathway, or the induction of tripartite motif-containing proteins (TRIMs), which degrade IRF3 and IRF7, or the induction of microRNAs, such as miR-146a and miR-155, which silence certain mRNAs which are key components of the pathway. Ultimately, type I interferons are cytokines that play a crucial role in the innate immune response, but also act at the interface of adaptive immunity [29, 30, 31] and, as such, need to be tightly regulated. When its signalling is aberrantly activated or sustained, it can lead to a variety of clinical manifestations, ranging from autoinflammatory syndromes to autoimmune disorders.
2. Neurologic disease in type I interferonopathies
Type I interferonopathies are a group of rare monogenic disorders characterised by constitutive activation of type I interferon signalling, leading to chronic inflammation and multiorgan damage. Severe interferonopathies, and typically the most frequent ones, are first and foremost neuroinflammatory disorders. The most common clinical signs of type I interferonopathies are neurological, affecting the central and peripheral nervous systems. These include developmental delay, intellectual disability, seizures, spasticity, ataxia, dystonia, neuropathy, and hearing loss. The exact incidence and prevalence of type I interferonopathies are for the most part unknown, but estimates place incidence between 1:10,000 and 1:1,000,000 [32, 33, 34]. While the exact percentage of each type I interferonopathy among the total cases is also uncertain, the most common is Aicardi-Goutières syndrome (AGS).
2.1 Aicardi-Goutières syndrome
AGS is an interferonopathy, typically exemplified as a neuroinflammatory encephalopathy resembling congenital viral infection. By most accounts, AGS is the most common of the interferonopathies, and the better studied [34]. Clinically, AGS can present as neonatal-onset AGS or late-onset. Neonatal-onset can often be mistaken for a transplacental-acquired infection. When evidence for an obvious infection is lacking, common practice is that AGS should be considered. Symptoms during the first few weeks of life include slowed cognitive growth, abnormal movements, ataxia, and epileptic seizures, as well as systemic signs of infection including persistent fever. Late-onset AGS is challenging as symptoms may occur several months later alongside otherwise normal infantile development. Slowed growth of head circumference, spasticity, and weakness may sometimes be readily apparent. Imaging in both early and late onset forms often reveals microcephaly, intracranial calcification, leukoencephalopathy, necrosis, vasculopathy with aneurysms, infarcts, and sometimes discernible haemorrhage [35]. On a histopathological level, acute demyelinating lesions reveal the extent of neurological damage, especially in late-onset patients, with diffuse demyelination reminiscent of acute demyelinating encephalomyelitis [36]. Microangiopathy is also a common occurrence [37, 38, 39, 40]. Calcium deposits form around the blood vessels, and it is thought that this is attributed to excessive cell senescence and apoptosis [41].
Type I interferons are found consistently in CSF and serum at the neonatal stage [17, 42]. As interferons display high bioactivity reflected by a short half-life, they are notoriously difficult to detect, and in the early days, cytopathic protection assays were performed. Simply, CSF from patients was found to contain sufficient interferons to avert toxicity associated with vesicular stomatitis virus challenge in a recipient cell line. Simple experiments first gave clues as to which interferon subtypes were present in patients with AGS, pinpointing IFNα as the principal culprit. Leaps in bioassay technologies have allowed detection down to 0.1 femtograms, confirming on average 1000-fold increase in IFNα compared to healthy individuals [42, 43]. Analysis of the largest AGS cohort to date reveals that significantly higher levels of IFNα in CSF are consistently found in earlier onset, more severe, disease supporting the notion of a detrimental role of type I interferons that is dose dependent [44]. Intriguingly, this is not observed consistently in serum [44] which supports that the production is central rather than systemic in AGS. Importantly, interferon-response gene expression has allowed the definition of an interferon-score, which is now a widely used, highly sensitive, rapid, cheap, and specific interferon metric [42, 45, 46, 47, 48, 49, 50].
Mutations in nine genes have been identified to this day, all of which are involved in nucleic acid detection and metabolism. Overall, loss-of-function mutations lead to deficiencies in the clearance of nucleic acids, while the gain-of-function mutations cause overt sensing of nucleic acids. Mutations in TREX1 [18], RNASEH2A, RNASEH2B, RNASEH2C [19], SAMHD1 [51], and ADAR1 [52] result in the accumulation of nucleic acids, sometimes derived from endogenous retroviral elements, which result in potent activation of nucleic acid sensors. In particular, TREX1 is an important exonuclease, whose inactivation leads to accumulated DNAs in the cytoplasm that trigger overexpression of type I interferons [18] through the cGAS-STING pathway [53, 54]. Beyond AGS, mutations have been described in systemic lupus erythematosus (SLE) [55] and familial chilblain lupus (FCL) [56], linking together AGS and lupus. Similarly, mutations in RNASEH2A/B/C, which form a protein complex that degrades RNA:DNA hybrids and excises incorrectly inserted ribonucleotide monophosphates during DNA replication, lead to DNA damage and enhanced generation of byproducts of DNA repair [57]. Accumulated DNA repair metabolites in the cytoplasm caused by RNASEH2 mutants stimulate the cGAS-STING pathway, resulting in AGS [58]. Lastly, mutations in LSM11 and RNU7-1, which encode two components of the canonical replication-dependent histone pre-mRNA processing complex, cause impaired processing of mRNAs [59]. This leads to the release of cGAS from nucleosomes, thus binding to proximal nuclear DNA, and activates the cGAS-STING-TBK1 pathway inducing the expression of type I interferons [59]. Lastly, mutations in ADAR1 cause aberrant activation of nucleic acid sensors MDA5 and ZBP1 through enhancement of recognition of endogenous retroviral elements and causing uncontrolled type I interferon production [60, 61, 62]. These mechanisms exemplify the importance of accurate regulation of endogenous nucleic acid sensing and how their loss-of-function inevitably results in overt type I interferon production. Similar aberrant responses can also happen with gain-of-function mutations. Mutations in IFIH1 have resulted in overactivity of its gene product, MDA5, causing it to bind to RNA more avidly [63, 64]. This mimics excessive nucleic acid sensing and also results in type I interferon overproduction. While the genetic mutations and genes affected are numerous, mechanisms of AGS are related to aberrant nucleic acid sensing and defective DNA or RNA degradation. Mutations that cause dysfunctional negative regulation also exist, leading to other encephalopathic interferonopathies with substantial clinical overlap.
2.2 Other encephalopathic interferonopathies
Though rare, many other encephalopathic type I interferonopathies have been identified. Loss-of-function mutations in ISG15 cause disease similar to AGS and SPENCD including calcifications of the cerebral basal ganglia and type I interferon signatures [65] but can also cause dermatologic disease as often seen with interferonopathies [66]. It is recognised that ISG15, itself an interferon-response gene, is important for limiting type I interferon production, and that disease in ISG15 deficiency is systemic, but the exact contribution to disease from within the brain is undetermined. Interestingly, it is through its interaction with USP18, mutations of which are also associated with AGS [67], that ISG15 can limit type I interferon signalling by displacing JAK1 from IFNAR [68, 69]. Importantly, in vivo loss of USP18 has been studied in rodents, and it was found to cause unabated – of otherwise tonic self-limiting – type I interferon signalling and to lead to the generation of over phagocytic microglia causing white matter damage and neurodegeneration [70].
Rare mutations in a lysosomal protein encoded by ACP5, also cause a type I interferonopathy called Spondyloenchondrodysplasia (SPENCD). It is characterised by skeletal dysplasia typified by vertebral abnormalities and metaphyseal lesions of the long bones. Concurrently, brain calcifications with neurological impairment, and high type I interferon signatures, reminiscent of classical AGS, are also observed [71, 72]. Little is known about the pathological mechanism, yet these mutations result in a highly penetrant monogenic systemic lupus erythematosus (SLE) manifestation [73, 74, 75], suggestive of a broader relationship between type I interferonopathies and lupus.
3. Encephalopathic non-monogenic type I interferonopathies
Systemic lupus erythematosus (SLE) is a disease driven by type I interferons and characterised by neuropsychiatric involvement. Interestingly, many overlapping psychocognitive disturbances are also observed as side effects from exogenous interferon therapies.
3.1 Neuropsychiatric involvement in lupus
Systemic lupus erythematosus is the historical and immunological archetype autoimmune disease, affecting multiple systems including the CNS. It is estimated that almost four million people worldwide live with SLE [76]. More than half of SLE patients exhibit some neuropsychiatric manifestation [77, 78] though the exact prevalence and list of symptoms describing it are debatable [79, 80]. It is associated with more severe cases as demonstrated by a threefold higher mortality rate than SLE patients without obvious neuropsychiatric affliction [78, 79]. Confusional state, anxiety, cognitive dysfunction, mood disorder, and psychosis are some common manifestations of neuropsychiatric lupus, delineating a group of syndromes [81]. Further evidence of neuronal involvement in lupus comes from increased neurofilament light (NfL) in both plasma and CSF [82, 83, 84]. NfL is a bonafide marker of neuronal damage that gets released and drained into the CSF, which pours out to the circulation, proportionally to the extent of axonal damage [85]. In SLE, NfL is further increased in patients with obvious neuropsychiatric involvement [83, 84] and correlates to neurocognitive and motor function [86].
SLE and AGS display some important commonalities that ultimately define both diseases as interferonopathies. Variants in TREX1, which cause AGS, also increase the risk of SLE [55, 87, 88], and particularly neuropsychiatric lupus [87]. Therefore, it is not surprising that type I interferons are strongly implicated in SLE [42, 89] and have been found to be pathogenic since targeting either IFNα [90, 91] or IFNAR signalling [92, 93] ameliorates disease progression. Higher IFNα in serum is also a strong predictor of mortality and correlates with neurological manifestations [94]. IFNα is also highly produced in CSF [43, 95, 96, 97], though it is unclear whether higher production in serum or CSF could inform on the central versus systemic source of type I interferon production [42, 43, 96]. As of yet, it is unknown whether targeting this pathway will be beneficial for neuropsychiatric lupus, but preclinical evidence suggests this.
Studying neuropsychiatric symptoms in mouse models of lupus is possible. However, similar to human studies, this aspect has been less investigated than its systemic disease counterpart. A lupus-prone mouse model overexpressing Tlr7 among other genes and exhibiting high peripheral type I interferon signatures [98, 99], also develop strikingly elevated interferon signatures in CNS [100]. Importantly, these mice exhibit anxiety and fatigue similar to clinical symptoms in humans. The response seems spatially restricted in high intensity patches across the entire brain, affecting predominantly microglia but also neurons and oligodendrocytes [100]. This is also seen in a different lupus-prone mouse model, where induced interferon-responses accompanying microglial activation [101] suggest conserved pathology affecting the CNS. Additionally, exogenous administration of IFNα precipitates lupus pathology [102, 103] and neurologic disorder including anxiety, depression, and cognitive impairment.
The mechanisms by which type I interferons cause or aggravate development of neuropsychiatric symptoms in SLE have not been exhaustively investigated. One proposed mechanism is through modulation of neuroactive metabolites. SLE patients with cognitive dysfunction are found to have increased quinolinic acid [104, 105, 106], to kynurenic acid ratios [107]. Quinolinic acid is an NMDAR agonist causing glutamatergic excitotoxicity [108, 109] and more so when favoured over kynurenic acid [110]. This metabolite balance dysregulation concurrently correlates significantly with type I interferon-response [111]. Quinolinic acid is metabolised from tryptophan and through indoleamine 2,3-dioxygenase (IDO) [112], an interferon-inducible enzyme known to mediate neurobehavioural alterations [113]. In SLE patients, IDO is induced in a type I interferon-specific manner [114]. This is paralleled by an increase in kynureine to tryptophan ratio in the circulation as IDO metabolises tryptophan into kynureine [107, 111, 114]. Loss of serotonin is also reasoned to be affected in a similar way. Serotonin is an important neurotransmitter that is also metabolised from tryptophan [115] and which is deregulated in human SLE [114, 116] and in the hippocampus of lupus-prone mice [117]. Increased IDO in SLE can explain the reduction of serotonin observed in the periphery [114], and it is arguable that a similar mechanism may take place in the CNS though this has yet to be demonstrated in SLE.
Overall, while a lot of what is known about the pathological mechanisms of neuropsychiatric SLE are inspired from findings from AGS, clinical evidence is highly suggestive that the type I interferon pathway may be therapeutically relevant for the neuropsychiatric manifestations as well as well as for systemic disease. The associations between neuropsychiatric lupus and AGS, and the teachings it has provided, are a testament to how rare monogenic neuroinflammatory disorders can provide aetiological insights into the pathogenesis of more common polygenic disorders. Importantly, more learnings can also be achieved from clinical experience with exogenous IFNα and IFNβ therapies.
3.2 Exogenous interferon treatment
Type I interferons have been used in the clinics to treat different diseases for many years, including hairy cell leukaemia, chronic myeloid leukaemia, hepatitis C virus infection, melanoma, multiple sclerosis, systemic mastocytosis, chronic hepatitis B virus infection renal cell carcinoma, and Kaposi’s sarcoma. Despite being used at refined therapeutic doses, psychocognitive side effects are common and have been well documented from 40 years of clinical experience with these cytokines [118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134]. Common side-effects in the short term include confusion, headaches, fatigue, myalgia, flu-like symptoms, and psycho-emotional disturbance. Longer treatment regimens often result in dementia-like outcomes [135, 136, 137, 138, 139, 140]. Furthermore, high dose versus low dose IFNα therapy much exacerbated signs and incidence rates [141], indicative of a dose-dependent effect.
Depression is the most common occurrence. Incidence among both IFNα- or IFNβ-treated patients is estimated to be 50%, even with optimised dosages, and prophylactic antidepressant therapy is often initiated pre-emptively [123, 128] though its true efficacy is still debated [142, 143]. Major depressive episodes are also commonplace and have been reported in as many as 30% of HCV patients treated [126, 133]. Resting state fMRI performed in a cohort of 22 patients with hepatitis C infection pre- and post-peripheral therapeutic dosing of IFNα revealed rapid and profound changes in the brain [144]. The altered brain functional network and reduced global connectivity efficiency correlated well with changes in anxiety, fatigue, confusion, and mood, reinforcing the immediateness of changes to neuronal networks. Importantly, while the majority of cases of IFNα-induced depression will achieve remission following discontinuation or end of therapy, this can take up to 3 years [125, 130, 133] indicating long-lasting neural changes. These figures may be underestimated due to the lack of long-term follow-up after treatment cessation [130, 133].
Assessing the adverse impact of IFNβ therapy on multiple sclerosis (MS) has been challenging, as MS itself leads to cognitive dysfunction [145]. Cognitive dysfunction in MS also correlates with depression and fatigue [146, 147], adding a further layer of complexity. In comparison, fingolimod is a superior therapy for MS, providing better outcomes for cognitive decline compared to IFNβ [148, 149, 150, 151, 152, 153]. Fingolimod causes immunosuppression as well as neuroprotection [154], an advantage over IFNβ which, specifically in MS, only exerts immunosuppression. It is therefore challenging to separate any neurotoxic effects associated with IFNβ. As new therapies are slowly making their way to more common clinical use in MS [155], more careful personalised medicine approaches can be achieved reducing long-term sequelae for patients.
The impact of type I interferons on psychocognitive states involves a complex, understudied, and multifactorial process involving changes in neuroactive metabolite balance, potentially hormonal dysfunction, brain microvascular dysfunction, and induction of psychoactive chemokines. As previously discussed, they potently induce IDO, which catalyses a key metabolic reaction that leads to the loss of serotonin and kynurenic acid, favouring the excitotoxic quinolinic acid [107, 113, 156]. Interferon therapies have also been found to induce thyroid dysfunction, ranging the entire spectrum of hypothyroidism, hyperthyroidism, and thyroiditis. Clinical thyroid disorders are frequently associated with psychiatric symptomatology [157, 158, 159, 160]. The exact prevalence is difficult to determine as few studies evaluate thyroid status, but it may be as low as 11% and high as 45% [161, 162, 163, 164, 165]. While thyroid hormones are known to exert biochemical effects on the brain, the bulk of the research conducted is descriptive rather than mechanistic. No significant correlation could be easily discerned between thyroid hormones and development of major depression induced by IFNα [161], perhaps suggesting parallel pathways. Nevertheless, given the systematic thyroid hormone imbalance induction by IFNα therapy, perhaps some degree of mood dysfunction may be attributable to it, though research is for now lacking.
Interferons can also directly act on the brain. In mice, it was found that peripherally administered IFNβ was sufficient to induce depressive symptoms [166], and that IFNAR activation on brain endothelial cells was responsible for the depressive symptoms. Activation of the BBB’s endothelial cell IFNAR pathway results in downregulation of adherens and tight junction transcripts causing endothelial dysfunction and exemplified by BBB leakage. Evidence of this is also perhaps apparent from the clinics. Thrombotic microangiopathy (TMA) is another serious side effect of interferon therapies [167, 168, 169] requiring immediate discontinuation and critical care. These events are associated with higher dose interferon therapy, and to result in leaky microvasculature accompanied by perivascular immune cell infiltration and narrowing of the endothelial cell lumen in human patients and in mice [168]. Chemokines CCL2 and CXCL10 are strongly induced by interferons in brain endothelial cells [166], providing a plausible explanation for the microvascular changes and infiltration. Of note, it is the microangiopathy that is the dominant brain characteristic, as also observed in neuropsychiatric lupus [170], and thrombosis is instead a far less prominent feature [168]. As not all microvessel damage is visible by MRI, it is unclear whether subclinical cerebral vascular damage is happening throughout all interferon-treated patients, thus widely contributing to the psychocognitive dysfunction induced by type I interferons. Lastly, activation of CXCR3 signalling in neurons by brain endothelial cell-derived CXCL10 elicits changes in synaptic plasticity responsible for the depressive phenotype in vivo and in vitro causing weakened synaptic long-term potentiation in hippocampus [166, 171].
Genetic associations between type I interferon-induced depression and gene variants exist, but knowledge is for now limited. One study linked polymorphisms in cyclooxygenase 2 (COX2) or phospholipase A2 (PLA2) with a more than three-fold increased risk of developing depression [172]. Intriguingly, an association in patients with major depression not induced by interferon therapy could also be made, suggesting some similar underlying mechanisms [172]. In line with this observation, IFNα-induced depressive symptoms could be mitigated in mice treated with non-steroidal anti-inflammatory drugs (NSAIDs) inhibiting COX1/COX2 [173]. This is an important consideration in light of reported anti-depressive effects of NSAIDs [174, 175] and of enhanced efficacy when used in combination with anti-depressants [176].
Interestingly, type I interferon signatures can also be found in major depression not induced by interferon therapy [177, 178]. Prototypical ISGs such as MXs, OASs, IFITs, ADAR, and CXCL10 [179] are found upregulated in the circulation of patients. It is unclear whether type I interferons might be causative; however, this would argue for a detrimental role in major depression. Depression is also suggested as a trigger for Alzheimer’s disease and cognitive decline [180], raising important additional implications. In one study, an association was found between the Apolipoprotein E ε4 (APOE4) allele, which confers greater risk of Alzheimer’s, and higher incidence of interferon-induced neuropsychiatric symptoms [181], suggesting a link between type I interferons, depression, and Alzheimer’s disease.
The neurocognitive impact of exogenous therapy with type I interferons is well-recognised, and despite systemic administration routes and refined dosages, patients exhibit often debilitating and dangerous psychocognitive side-effects. While anxiety and depression can be partially mitigated, psychomotor dysfunction, fatigue, and confusion are difficult to alleviate [140]. Over the years, the standard of care for many of these indications is moving away from IFNα an IFNβ therapies, both as first-line therapy and often entirely. The advent of more efficacious, and safer direct-acting and all-oral antivirals [182, 183], checkpoint blockade inhibitors [184], and immunomodulating therapies [155, 185] has allowed a consistent phasing out of interferons in clinical care.
4. Translation to more common neurodegenerative diseases
There is growing interest in understanding neuroinflammation in rare diseases because it represents a promising and translatable therapeutic target, also for more common neurodegenerative disorders. Neuroinflammation is recognised as a key hallmark of diseases such as Alzheimer’s and Parkinson’s disease. While the role of type I interferons in these diseases remains to be fully understood, several lines of evidence suggest their implication in their disease process.
4.1 Alzheimer’s disease
Alzheimer’s disease (AD) is the most common cause of dementia, affecting more than 50 million individuals worldwide. It is characterised by gradual cognitive decline and behavioural changes due to chronic neurodegeneration, and predominant impairment of anterograde episodic memory. Individuals over the age of 65 are most commonly affected, representing 90 to 95% of all AD cases. Overall, age is the strongest risk factor for AD suggesting that the ageing process is strongly implicated [186]. Early-onset AD (EOAD) affects individuals below the age of 65 and is known to be caused by one of a handful mutations. The discovery that certain mutations in the amyloid precursor protein APP gene [187, 188] or the presenilin 1 [189] and 2 [189, 190] (PSEN1 and PSEN2) genes, encoding the enzymes cleaving amyloid peptides, cause EOAD has galvanised the field and concomitantly allowed headway in the understanding of late-onset AD (LOAD). As aggregated misfolded amyloid β-containing extracellular plaques are a major pathologic hallmark of AD, the understanding of the amyloid misfolding and aggregation processes have led to major strides for elucidating the pathology. This is also thanks to the generation of mouse models with abnormalities in APP processing mimicking human EOAD [191]. After decades of therapeutics research, and at the time of writing, two biologics targeting amyloid deposits have been approved for therapy following modest but positive trial outcomes [192, 193]: aducanumab and lecanemab.
Subsequent work has identified and proposed many other components importantly implicated in AD. One such component is the protein tau. Tau, like Aβ, has a propensity to misfold, aggregate, and spread, and mutations in its gene, MAPT, have been identified in familial inherited tauopathies such as frontotemporal lobar degeneration with tau inclusions (FTLD-tau) [194]. Hyperphosphorylation is another key feature of tau and a marker of severity of neuronal pathology [195, 196]. Intracellular tau protein-containing neurofibrillary tangles are found in brain regions related to clinical symptoms and to better correlate with pathology than amyloid burden [197, 198], leading to believe that it may be directly implicated in the pathogenesis [199].
Aside from APP, PSEN1 and PSEN2, and MAPT, APOE is the most important risk factor for AD [200, 201, 202]. Certain alleles substantially increase risk (E4/E4: 12-fold increase) while others confer resistance (E2/E2: 2.5-fold decrease), while others are the common variants (E3/E3: no impact). The impact that APOE has on AD is likely even more intricate. An R136 mutation was identified in an individual carrying an autosomal dominant mutation in PSEN1, but which was protected from developing EOAD [203]. Named after the city in New Zealand where it was discovered, the Christchurch mutation confers resistance to AD by reducing tau pathology [204]. The genetics of EOAD are complex, but they have allowed many advances in our understanding of AD. Genetic research of LOAD also revealed new facets of AD, especially the involvement of the immune system.
Neuroinflammation is increasingly being recognised as an important component in the pathogenesis of AD. Genome-wide association studies performed on LOAD have implicated the immune system. Loci mapped to genes hypothesised to carry out immune, or at least microglial, function-related roles have been proposed such as ABI2, ACE, ADAM10, ADAMTS1, BIN1, CD2AP, CD33, CLU, CR1, HLA-DRB1, HLA-DRB5, IL34, MEF2C, MINK1, MTHFR, PCG2, PILRA, SHARPIN, SPI1, SORL1, TOMM40, and TREM2 [205, 206, 207, 208, 209]. Although more than 84 loci have been identified, they may not represent the full spectrum of risk variants for LOAD. As studies become larger and better powered for discovery of subtle associations, more are likely to be added to this list [209]. TREM2 is an important risk variant [210, 211] with consistently strong association and susceptibility risk, currently estimated to three- to four-fold increase [212]. One heterozygous R47H variant represents the highest risk for AD aside from familial mutations and APOE alleles, and has therefore been studied extensively despite sometimes contradictory results [213, 214].
AD is a multifactorial disease with complex cellular interactions that culminate in neuronal cell death. Numerous mouse models have allowed studying the pathogenesis of AD at the molecular and cellular level. Coupled with the advent of single-cell transcriptomic technologies [215], they have permitted a better understanding of the cellular states during AD and have allowed characterisation of virtually all brain cell types. Across AD models, microglia cell types have been identified and characterised according to their transcriptomes and consistently classified as “homeostatic”, “disease associated microglia” or “DAM”, and “type I interferon-responsive microglia” or “IRM” [216, 217, 218, 219, 220, 221]. A lot of excitement was generated from research performed describing the DAM subsets in mice as they are believed to define a distinctive neurodegeneration microglial cluster [222, 223]. However, a clear and consistent DAM cluster has been difficult to pinpoint in humans [224]. IRM have been described in human AD, and the subset is found to be associated to microglia exhibiting endolysosomal dysfunction, cytoplasmic dsDNA, and activated morphology [224]. This same IRM subset also carries significant differential expression of genes associated with genetic risk for AD, such as APP, APOE, GRN, CD33, and C4A and hence is reasoned to be a putative target for therapeutic intervention [224]. While it is now clear that clues relating to presence of type I interferons are seen throughout human AD [224, 225, 226, 227, 228, 229], its role can only be studied using mouse models.
Similar to human AD, type I interferon signatures can be found across different AD models of either amyloidosis, tauopathy, or combinations of the two [217, 220, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238] and despite differences in affected brain areas, temporal and cognitive pathology evolution, and disease mechanisms, suggesting conserved induction pathways. Importantly, genetic loss of IFNAR or targeting via monoclonal antibody is protective for the overall progression [228, 229, 232]. In an APP/PS1 mouse model, loss of IFNAR signalling leads to significant amelioration of the spatial memory deficits, and inhibition of inflammation and microgliosis markers, while astrocytes exhibit activation potentially as a compensatory mechanism [232]. These observations were accompanied by complete loss of interferon-signalling, as expected, but also of IFNα expression hinting at a potentially self-sustained pathway in AD [232]. Similarly, blockade of IFNAR signalling by delivery of a monoclonal antibody to the cerebral ventricles, thus bypassing the BBB, leads to significant reduction in microglial activation [228]. IFNAR signalling is similarly detrimental in tauopathy models [237]. Loss of IFNAR causes strikingly reduced tau hyperphosphorylation and inflammatory cytokine and chemokine production in vivo and in vitro stimulation of neurons with IFNα or IFNβ exacerbates tau hyperphosphorylation and seeded tau aggregation [237]. Furthermore, tau triggers the generation of interferon-responsive oligodendrocytes in vivo, as evidenced by single cell analyses [239], though their contribution to disease remains to be elucidated. Further evidence that tau drives disease through type I interferons comes from deeper investigations of the protective effects of the Christchurch APOE mutation [240]. Mice carrying tau mutations and the human E3/E3 Christchurch mutation were protected from tau pathology by loss of cGAS-STING-induced type I interferon production. While the complete mechanism is still unclear, microglia carrying the protective mutation had suppressed production interferons [240]. Other mutations commonly found in AD were also linked to type I interferons. Concurrent loss of function of TREM2 in tauopathy and amyloidosis AD-prone mice causes exacerbation of the type I interferon signatures, along with more pronounced tau aggregation, hyperphosphorylation, and neurodegeneration [220]. This is paralleled by findings in individuals carrying TREM2 variants R47H and R62H, which have a strongly increased AD risk, and concurrent enhancement of type I interferon signatures compared to TREM2 common variants [241, 242]. It is still not demonstrated whether these AD associated variants exacerbate pathology through IFNAR signalling, though mouse models of tau pathology with TREM2 R47H-carrying variants recapitulate enhanced IRM [234], and this is through an increased responsiveness to triggers of type I interferon production [241].
The induction of type I interferons in AD is thought to be mediated by an amyloid-facilitated nucleic acid recognition process. Nucleic acids are found on and around amyloid plaques in human and mouse models [228, 243, 244, 245, 246], which is probably linked to charge complementarity. Microglia, due to their phagocytic activity, actively take up oligomeric amyloids containing nucleic acids, which then signal to nucleic acid sensors leading to production of type I interferons [228]. Neurons are also capable of producing IFNα and IFNβ in response to Aβ peptide stimulation directly and without exogenous nucleic acids, and to do so via MyD88 and IRF7 [247], raising the prospect of a parallel pathway of mitochondrial or nuclear nucleic acid release following cell damage. cGAS-STING is also found to be expressed and induced in AD-prone mice across different neuronal cell types and is likely a key nucleic acid sensor mediating the production of type I interferons in response to amyloids [248, 249] but possibly not the only one.
Clearance of nucleic acids, whether following uptake or whether released subsequent to nuclear or mitochondrial damage, is an important process. Genetic loss of these mechanisms can result in severe diseases, including type I interferonopathies. Phospholipase D3 (PLD3) is an exonuclease that degrades mitochondrial DNA limiting exaggerated TLR9 [250, 251] and cGAS-STING [251, 252] responses which result in the induction of type I interferon production. Importantly, rare variants in PLD3 have been discovered to increase risk of AD [253, 254], and potentially in EOAD [255] suggesting that defective nucleic acid nuclease activity could be implicated in AD and cause aberrant triggering of type I interferons. PLD3 is indeed found deregulated in AD [256, 257] and accumulated in neuritic plaques [257], suggesting a defective intracellular exonuclease function. Another protein involved in clearance of nucleic acids is 2’,5’-oligoadenylate synthetase 1 (OAS1). OAS1 is a type I interferon-inducible protein which, through its interaction with RNaseL, is known to degrade dsRNA and limit viral infection but to also limit sensing of intracellular RNAs [258, 259]. While the role of this interferon-inducible protein in the pathogenesis of AD still not known, risk variants have been identified suggesting that it may be implicated in the disease process [260, 261].
As for how type I interferons mediate neurodegeneration in AD, there are multiple mechanisms demonstrated so far. For one, Aβ stimulated IFNAR deficient glia produce significantly less or no inflammatory cytokines, including IFNα and IFNβ, compared to IFNAR sufficient glia, and transfer of conditioned media to neuronal cultures demonstrates a neurotoxic activity that requires IFNAR signalling [232, 262]. One way by which IFNβ has been proposed to be directly neurotoxic [263, 264] is through mitochondrial destabilisation [265]. Furthermore, IFNβ induced by nucleic acid recognition also cause further upregulation and hyperactivity of DNA sensors in microglia [266], suggestive of a self-propelled activation loop. Type I interferons also cause inhibition of Aβ peptide phagocytosis by microglia, suggesting that decreased clearance of reactive amyloid species could also exacerbate neuroinflammatory outcomes [262]. In vivo, IFNAR signalling activation leads to complement-driven elimination of synapses [228, 229], an effect that seems entirely driven by microglia, and likely mostly ones near plaques and co-expressing CLEC7 and AXL [229].
Ageing is the most important risk factor for AD. Type I interferons have been associated with brain ageing [267, 268] and are therefore thought to also impact AD through processes in common with ageing. One identified process is through inhibition of the transcription factor Myocyte-specific enhancer factor 2C (MEF2C) [233, 249, 268]. MEF2C is involved in neuronal signalling, differentiation, and integrating memory formation [269, 270, 271]. Moreover, polymorphisms of the MEF2C locus have been identified in AD repeatedly across studies and cohorts [205, 272, 273, 274]. Type I interferons cause an inhibition of MEF2C during normal ageing which results in deteriorating cognitive function including learning and spatial memory and exacerbated neuroinflammation [268]. In AD-prone mouse models, both amyloid- [233] and tauopathy-based [249], type I interferons caused the downregulation of MEF2C leading to increased microglial activation, increased synaptic loss, and cognitive dysfunction.
However, the detrimental effects of IFNAR signalling in AD are likely not mediated solely by microglia. Neuronal, but not microglial, IFNAR signalling contributes to amyloid plaque formation in AD-prone mice, a mechanism suggested to be mediated by the interferon-induced transmembrane protein 3 (IFITM3) [229]. IFITM3 is an interferon-inducible protein that binds to the γ-secretase complex responsible for Aβ cleavage from APP and enhances its activity [275]. It is overexpressed in AD as well as mouse models, in line with the overexpression of other type I interferon stimulated genes, and loss of function leads to striking reduction in plaque density [275] supportive of the observation that IFNAR signalling in neurons participates in amyloid plaque deposition [229]. Certain variants of IFITM3 are also significantly associated with cognitive decline, amyloid and tau burden and brain atrophy [276], though it remains to be demonstrated how these variants affect the amyloid processing-associated function of IFITM3. Neurons also respond directly Aβ by producing IFNα and IFNβ through MyD88-IRF7, a pathway which sensitised to concurrent neurotoxicity [247].
Evidence points to a predominantly detrimental role of type I interferons in BBB integrity. Interferon signatures in brain endothelial cells are elevated in AD-prone mice [277]. IFNβ directly increases endothelial cell permeability to large molecules, downregulating intercellular cadherins [277] and suggesting a direct consequence on BBB leakiness. Evidence is lacking in vivo, however, and it remains to be fully elucidated whether this can be replicated in endothelial cell targeted IFNAR-deficient AD-prone animals. This is especially important as there is contrasting evidence indicating that systemic IFNβ therapy in the context of MS participates in restoring BBB integrity [278]. It is unclear whether this is an indirect effect on the BBB via immunoregulation or a direct effect on endothelial cells. Different models of cerebrovascular damage [279, 280] and infection [281, 282], both of which trigger local type I interferon production by endothelial cells via cGAS-STING, demonstrate a detrimental role on BBB permeability. Thus, elucidating the role of type I interferon signalling according to the disease context and elucidating whether local and systemic effects may have opposing functions is important in understanding AD-associated BBB.
Type I interferon-induced CXCL10 has also been implicated in dementia associated with TAR DNA binding protein-43 (TDP-43) pathology. TDP-43 is an RNA interacting protein whose function is regulation of splicing, trafficking, and stabilisation of RNA [283]. Its normal function is lost in about 50% of frontotemporal dementia (FTD), a progressive neurodegenerative disease characterised by neuronal intranuclear and cytoplasmic inclusions [284, 285]. Loss of the normal function of TDP-43 triggers the production of type I interferons via dysregulation of normal RNA sequestration causing accumulation of dsRNA leading to activation of RIG-I [286] and by destabilisation of mitochondria causing mtDNA release and triggering of cGAS-STING [287]. This results in neurodegeneration in vitro and in vivo [286, 287, 288], and one proposed mechanism is through type I interferon-induction of CXCL10 and signalling to hippocampal presynaptic terminals overexpressing CXCR3 [288]. This triggers sustained neuronal hyperactivity and memory deficits in vivo [288]. It is not yet known what exactly causes upregulation of CXCR3 in neurons in the context of TDP-43 pathology, but clues of a TDP-43-type I interferon-CXCL10 pathway can be seen in human [287, 289, 290, 291]. It is noteworthy that TDP-43 pathology is also observed in about one-third of AD cases [292, 293] suggesting overlapping mechanisms with AD potentially via this identified axis.
Another CXCL10-driven mechanism involves CD8 T-cell infiltration [294, 295, 296]. In recent years, there has been new appreciation for the role of T cells in AD [297, 298]. Evidence now suggests that a CXCR3-CXCL10 axis exists for the recruitment of CD8 T cells, exacerbating neuronal damage and possibly also directly contribute to interferon signalling enhancement, and that this activity converges through the IFNAR1 [296]. The exact role of CD8 T cells in vivo in AD remains for now still elusive [296, 299], yet interferon-responsive CD8 T cells seem to be a common feature among amyloid [296] and tauopathy [300] models of AD. While microglia far outnumber CD8 T-cells in the brain, both in human AD and models, more work will be needed to discriminate between the type I interferon-driven recruitment and activation of CD8 T cells through CXCR3-CXCL10 mechanisms, and the type II interferon-mediated recruitment self-enhancement.
4.2 Down’s syndrome
Down’s syndrome (DS) occurs when an individual has an extra copy of chromosome 21, a phenomenon called trisomy 21. It is characterised by intellectual disability and developmental delay, and a striking incidence of early-onset AD (EOAD). The notable increase in life expectancy of individuals with DS has revealed dementia and other co-occurring neurological and immunological conditions. By age 40, half of the individuals develop AD, this increases to 77% by age 60, and virtually all develop AD by age 70 [301, 302]. Individuals also display important immune dysregulation [303, 304], with notable neuroinflammation [305] and resembling an interferonopathy [306, 307]. A higher prevalence of depression is also seen in DS, and this is associated more strongly with dementia [301, 302]. In addition, basal ganglia calcification is also found in 10–45% of individuals, [308, 309, 310, 311, 312, 313, 314] an observation that is not fully understood but thought to be attributed to an accelerated ageing process. While it was expected from a clinical perspective that DS ageing is accelerated, as evidenced by accelerated hair greying, decreased skin flexibility, and premature death among others, epigenetic age of both brain tissue and blood is confirmed from a molecular marker standpoint [315]. The epigenetic clock used to objectively assess ageing is based on a quantitative assessment of DNA methylation [316]. As a measure of ageing, it stands out among existing epigenetic clocks also because of its impressive predictive ability for time-to-death which further validates the approach [317, 318]. The ageing process is significantly accelerated circulating cells in DS, a process called immunosenescence [319], and this is further accentuated in brain [315].
Chromosome 21 carries ca. 200 genes, triplication of which causes DS and accompanying disease. Deconvolution of the specific role of each gene in DS is difficult. Triplication of APP gene is attributed as the main reason for EOAD, including accompanying senile plaque deposition paralleling genetic AD [320]. The IFNAR1 and IFNAR2 genes which form the two active chains of the functional IFNAR are also found on chromosome 21. Complicating interpretation, however, the interferon gamma receptor 2 (IFNGR2) chain and the interleukin 10 receptor beta subunit (IL10RB) genes are also found on chromosome 21, one of the two heterodimers of the type II and type III receptors, respectively, and whose signalling overlaps substantially with type I interferon signalling. Nevertheless, much research has been carried out on the role of interferons in DS.
Firstly, cells isolated from DS individuals are more reactive to exogenous IFNα or IFNβ treatment demonstrating that the addition of an additional fully functional set of IFNAR receptors leads to an expected increased signalling [304, 306, 321, 322]. Remarkably, signalling downstream of IFNAR is not overcome by negative regulation, and no desensitisation is apparent [304]. However, it is argued that inappropriate and mistimed responses are likely to occur [322]. Importantly, IFNAR triplication also has consequences in vivo in patients. DS individuals display significant correlation between IFNAR1 and inflammation markers including CRP and inflammatory gene signatures [323] as well as of the interferon-response signatures [307, 323]. Furthermore, systemic interferon signatures correlate with cardiovascular severity and depression [307] suggesting that increased interferon signalling associates with a more severe phenotype. While the increased interferon-response and dependence on JAK/STAT signalling seems obvious considering what precedes, the mechanism responsible for triggering of increased type I interferon production remains elusive. One hypothesis is that the aneuploidy state itself fundamentally triggers type I interferons via cGAS-STING signalling due to accumulation of dsDNA in the cytosol [324]. This provides a rationale for the mechanism of triggering type I interferon production in DS, though this remains to be specifically demonstrated.
To investigate mechanistically the role of type I interferons in DS much work has been performed using engineered mice that mimic the trisomy of chromosome 21. Early experiments showed overall amelioration of the phenotype by neutralisation of a cocktail of anti-interferon antibodies with DS mimicking mice available at the time [325]. Currently, numerous DS models exist, but the Dp16 model is often deemed superior. It is trisomic for the entire mouse chromosome 16 region, which includes approximately 113 orthologs found in human chromosome 21, and importantly excludes any orthologs of genes not found on human chromosome 21 [326]. While the same difficulty in distinguishing the contribution of each of type I, II, and III interferons exists in this DS mouse model as it does in human, it is found that the IFNAR receptor is overexpressed among all three interferon receptors and widely expressed in immune cells [323], mimicking the human condition [304]. Importantly, loss of the interferon receptor locus leads to spatial memory rescue and accompanying normalisation of synaptogenesis and dopamine receptor signalling [323].
Taken together, this research suggests a mild form of interferonopathy in DS [306]. It is important to better understand the clinical evolution of disease and define the pathogenic mechanisms to better guide clinical decisions. The predictable chronological sequence of DS allows for the rigorous investigation of the events preceding amyloid deposition and eventual neurodegeneration, making DS an important condition to further elucidate neurodegenerative diseases such as AD.
4.3 Inflammaging
Cell senescence is perhaps the most evident hallmark of ageing. Over the past 10 years, chronic low-grade inflammation has become recognised as an important addition to the hallmarks of ageing in a process dubbed “inflammaging” [327, 328]. Brain ageing, however, remains a challenging field and most research is performed using animal models.
To elucidate the molecular culprits of brain ageing, Michal Schwartz and colleagues performed transcriptomics profiling of various organs from aged mice and found selective upregulation of type I interferon signalling in the choroid plexus [267]. The choroid plexus is a critical structure in the brain that serves as a hub for neurovascular communication and as principal producer of CSF [329]. It would follow that consequences in the choroid plexus may affect wider brain activity. What the group found is that, not only are type I interferons overexpressed, they are also responsible for negatively affecting cognitive function and hippocampal neurogenesis during ageing. This was confirmed by other groups that found IFNα levels in CSF to significantly positively correlate with ageing-induced memory deficits in mice [231]. Blocking IFNAR signalling by delivering function-neutralising antibodies into the CSF via intracerebroventricular administration reduces interferon signalling in the choroid plexus. This leads to the restoration of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF1). It also inhibits microgliosis and astrocytosis in the hippocampus, demonstrating the extensive harmful effects of ageing-induced type I interferons in the brain [267]. Importantly, type I interferons and interferon responses are also seen in human, in elderly individuals [267], but more research is needed to characterise the ageing responses in the choroid plexus and the consequences for neurocognitive and memory processes. Other lines of evidence suggest that interferon signalling in the choroid plexus has implications for neurodegeneration. During the COVID-19 pandemic it was noted that patients that exhibited severe respiratory symptoms also developed neuropsychiatric [330], neurocognitive [331, 332], and fatigue [333] symptoms at a significantly higher rate. It is suggested that cognitive dysfunction caused by COVID-19 may also be linked to aberrant type I interferon production in the choroid plexus [334] as evidenced by chronic interferon-responses during severe COVID-19 [335]. AD patients also exhibit ageing-related inflammation in the choroid plexus [336], which is also paralleled in a mouse model of AD [231], though more work is needed to define whether type I interferons are involved in ageing-associated AD changes in the choroid plexus.
Exactly how type I interferons participate in the aberrant process of inflammaging remains to be fully elucidated. One proposed mechanism is through suppression of anti-oxidative factors. In mice, mitochondrial instability due to old age leads to type I interferon responses via mitochondrial DNA release and activation of cGAS-STING [337, 338, 339, 340]. The induced type I interferons then counteract NRF2, a potent antioxidant, leading to accumulated ROS and oxidative stress across different organs including heart, liver, kidney [339], and lung [341]. Although this mechanism has not been specifically demonstrated in the brain, studies in the retina and CNS indicate a similar ageing-related mechanism induced by interferons that leads to ROS [340]. Furthermore, cGAS-STING-type I interferon signalling also leads to anaemia by increasing inflammatory monocyte expansion and haemophagocytosis [339], something that could contribute to low grade chronic brain hypoxia [342].
Another mechanism proposed is linked to the senescence process. Senescence describes the abnormal state of permanent cell-cycle arrest, typically in response to stress or damage, and which is ultimately responsible for ageing [343]. Senescent cells also exhibit a senescence-associated secretory phenotype (SASP), releasing cytokines, chemokines and other molecules that can lead to tissue degeneration and a decline in organ function. Work performed to discover ageing-associated processes in the brain found that type I interferon signatures are specifically enriched across all neuronal cell types during ageing in mice, marking a unique signature capable of resolving chronological age [344]. This includes neural stem cells, a cell type vital for neuron renewal, maintenance, and repair, which also exhibited type I interferon signatures with its top gene being Ifi27 [344]. Sophisticated work has been performed to understand how a senescent state occurs. Retrotransposable elements (RTEs), remnants from ancient retroviruses that have integrated permanently into the genome, become more active during cell senescence. This intriguing process is also believed to be a strong contributor to somatic retrotransposition in the brain, a process important for neuronal somatic mosaicism [345, 346, 347]. It is found that senescent cells downregulate TREX1, leading to accumulation of RTEs which then triggers cGAS-STING and strong induction of type I interferons [348, 349]. This explains the interferon signatures found in senescent cells and during ageing, and is therefore a great marker, but evidence suggests that they are also responsible for triggering senescence and ageing [268] through cGAS-STING [350]. Type I interferons are notorious for promoting cell cycle arrest and inhibit proliferation [258, 351], an antiviral tactic meant to slow down viral spread. They are also potent inducers of chemokines and other cytokines. Hence, it stands to reason that chronic overexposure may also itself participate in the senescence process. Indeed, microglia from DS have been found to enter a senescence programme along with type I interferon overexpression, and remarkably inhibition of this signalling prevents development of senescence [352]. Similar processes have been observed in the senescence of haematopoietic and germinal stem cells [353], as well as hepatic stellate cells [348], indicating a potential universal mechanism. In the brain, a mechanism whereby microglia are responsible for triggering senescence in neurons and other glial cells is now hypothesised to be a major driving force behind cognitive impairment both in ageing, AD, and during brain injury [354, 355, 356]. One proposed mechanism of type I interferon-driven ageing of microglia is through the downregulation of the protective and inflammation-limiting transcription factor MEF2C [268]. MEF2C is found to be implicated in brain development and neuropsychiatric disorders [357, 358]. Chronic production of IFNβ in the brain causes downregulation of MEF2C, as does ageing, and in so doing inhibits a resilience to ageing-induced [268] and disease-induced cognitive decline [249]. Lastly, two recognised pro-ageing SASPs which promote decreased hippocampal neurogenesis, synaptic plasticity, impaired learning and memory and increased microgliosis, are CCL11 and CCL2 [359, 360]. There is evidence demonstrating that type I interferons are inducers of CCL2 and CCL11 [ 166, 171, 361, 362], though it remains to be demonstrated whether type I interferons promote ageing and senescence also through CCL2 and CCL11.
4.4 Brain trauma
Traumatic brain injury (TBI) was once thought to cause static neurological damage. Yet, research now indicates that it can set off a chain reaction leading to ongoing neurodegeneration, widespread damage outside mechanically injured sites such as the hippocampus [363] and the onset of dementia. It is common for individuals to suffer prolonged cognitive deterioration, which can be attributed, to some extent, to the emergence of dementia and AD following concussive injury [364]. Large cohort and meta-analyses have attributed a 1.5-4 fold relative fold risk increase in dementia following TBI depending on number of concussive events, and time following the event [365, 366]. This effect is exacerbated in the elderly, as both functional outcome and survival are significantly worse in elderly individuals, making age one of the more reliable prognostic factor [367, 368, 369]. Older individuals also represent the highest proportion of TBI events [370], adding further credence to the need for enhanced care for the advanced age groups. Progressive neurodegeneration due to TBI may account for 5–15% of all cases [371], suggesting that understanding the pathological mechanism of TBI may lead to better treatments and a staggering reduction of incident neurodegenerative diseases.
Neuroinflammation is known to cause secondary injury progression following TBI, potentially leading to long-term sequelae and progressive neurodegeneration [372, 373]. Much effort has been made to characterise the inflammatory environment of TBI in carefully controlled conditions, and to investigate the contribution of identified pathways to the long-term outcomes. For this purpose, preclinical research in the mouse has been instrumental, providing a broadly homogenous induction and allowing for experimental therapies, a feat that is difficult to achieve in emergency medicine settings involving humans. Multiple lines of evidence have now identified the type I interferon pathway to be strongly implicated, both by spatial [374], single cell [375, 376, 377, 378, 379], microdissected tissue [380], as well as bulk [280, 381, 382] transcriptomic analyses. While expression of interferon-response genes is widespread across microglia, meningeal macrophages, astrocytes, and oligodendrocytes, most evidence points to microglia and macrophages as the main producer of type I interferons following injury. Importantly, activation of the type I interferon pathway is detrimental to the resolution process, as consistently evidenced across genetic ablation models and through intervention by monoclonal antibody treatments [382, 383, 384]. Pharmacologic inhibition or genetic ablation of cGAS-STING also cause abrogation of type I interferon signalling and confers neuroprotection and accelerated neurocognitive amelioration [379, 385, 386, 387, 388] suggesting that aberrant DNA sensing through microglial STING may be a critical trigger for sustained and pathogenic inflammation following TBI. Activation of transposable elements as well as mitochondrial DNA release is found to trigger activation of cGAS-STING in this context [377, 389]. Other sources of nucleic acids, as well as nucleic acid sensors, are also likely to be involved. Neutrophil extracellular traps (NETs) have been found to be important in triggering neuroinflammation in TBI [390] and are triggers for TLR9 and type I interferon production [391].
Consistent evidence of the implication of this pathway is also seen during human TBI, despite high heterogeneity compared to preclinical models. Expression of STING1 is significantly upregulated following trauma, both at the site of injury and at the contralateral side [385] confirming its potential implication in the detrimental neuroinflammatory process. Upregulation of IFNβ, but not IFNα, is also seen within the first 6 h post TBI in patients that succumbed to the trauma [383], though it remains to be determined whether this partiality for IFNβ is maintained during the secondary, chronic neuroinflammation. Furthermore, nucleic triggers for the cGAS-STING pathway and for other nucleic acid sensors are highly enriched following TBI. Cell-free nucleic acids have been found in enormous amounts in both CSF [392] and plasma [393], and correlate with severity of trauma and outcome following injury. The extent to which nucleic acids pour from the brain to the CSF and circulation is a testament to the excessive cell death and accompanying nucleic acid release, and highlights the quantities that must be present in parenchyma during the acute event and therafter. With such excess of type I interferon triggering molecules, it is not surprising that interferon responses are also apparent, evidenced from human single-nuclei transcriptional analyses [377]. Lastly, the more severe outcomes seen in elderly individuals may be paralleled by enhanced persistence of type I interferon signalling and worsened outcomes observed in aged mice [378, 380, 394] and may provide a model for uncovering age-related determinants of interferon-driven chronic neurodegeneration following TBI.
Mediating the pathogenic activities of the cGAS-STING-type I interferon pathway is likely to involve multiple downstream events. Evidence suggests that effector T-cell infiltration via CXCL10 is one important component, whereby infiltrating CXCR3+ Th1 cells cause white matter injury, promoting anxiety and depressive neurocognitive changes [395]. Neuron loss in the hippocampus could be attributed to sustained chronic IFNβ [384], yet exact mechanisms remain to be elucidated. NOX2, a subunit of NADPH important for the production of ROS, is highly neurotoxic during TBI [396, 397, 398] and particularly in the hippocampus. Loss of IFNβ significantly attenuates NOX2 [384], implicating the type I interferon pathway in pathogenic ROS production. Neutrophils, which are important producers of ROS, can in fact be instigated to produce ROS following IFNα stimulation [399]. One possibility is that type I interferons exert control over ROS production via infiltrating neutrophils, which are generally regarded as detrimental in a sterile injury context in the brain [400]. Adding further weight to this hypothesis is the observation that neutrophil infiltration is significantly decreased in microglial STING deficient animals during TBI [387]. However, neutrophil infiltration is thought to be a self-limiting event, which may not carry over during the secondary, chronic neurodegeneration phase. Thus, another possibility is that interferons carry ROS production over through chronic phases via exerted control over IDO [156]. IDO is known to be induced by type I interferons in microglia and to result in production of ROS in response to infection [156, 401]. Thus, in the context of unabated type I interferon signalling, microglial damage of neurons may be mediated by IDO-dependent ROS production.
TBI induces strong immediate damage and a neuroinflammatory response that is detrimental to the long-term recovery via secondary injury processes. Although complex and multifaceted, the neuroinflammatory response is characterised by type I interferon signalling, albeit not exclusively. Yet, blockade of the pathway in preclinical models and the parallels seen in human suggest that targeting this pathway in human may hamper the aberrant neuroinflammatory process and may improve neurocognitive outcomes by reducing neurodegenerative processes.
4.5 HIV/AIDS-associated neurocognitive disorders
Human Immunodeficiency Virus (HIV) is the devastating virus that causes acquired immunodeficiency syndrome (AIDS), and which affects an estimated 39 million people worldwide. HIV uses the CD4 surface protein and either the CXCR4 or CCR5 receptors to gain entry into cells, thereby infecting them, and killing them in the replication process [402, 403]. Over time, this causes systemic immunosuppression as CD4 T cells, dendritic cells, monocytes, and macrophages become depleted. Due to advancements in the standard of care, which relies on antiretroviral therapy (ART), AIDS has become a secondary concern as viral replication is inhibited and infected individuals live longer lives without developing immunosuppression. While viral replication is effectively hampered, infection persists.
HIV/AIDS-associated neurocognitive disorders (HAND) are a common occurrence among people with HIV. Meta-analyses suggest a combined prevalence of 50% among all infected individuals, presenting with at least one neurocognitive sign among all seropositive individuals. Of those, cognitive-motor disorder (60%), major depression (15-40%), and delirium (17%) [404] are some of the neurologic complications of HIV. The prevailing theory is that infected cells serve as a ‘Trojan horse,’ transporting HIV to the brain, and causing infection of microglia [405], and astrocytes by cell-to-cell transfer [406, 407]. Remarkably, while ART can reduce the prevalence of HAND, incidence remains abnormally high and a concern for virtually all HIV patients, a fact probably explained by increased longevity [408, 409]. This suggests that neurocognitive decline in HIV patients despite controlled viral load may have similar mechanisms as age-related cognitive decline.
A complete picture of the pathological mechanism behind neurocognitive disease in HIV is lacking. Its pathogenesis is attributed to persisting viral load in the brain, unabated neuroinflammation, and neuronal loss due to pro-inflammatory cytokines. Microglia and brain infiltrating macrophages serve as the main reservoirs following HIV neuroinvasion, typically within two weeks after infection. Gene expression profiling of brain samples from seropositive individuals that had neurocognitive impairment reveals strong type I interferon-response genes such as OASs, IFITs, IFITMs, and CXCL10 across multiple studies [410, 411, 412, 413, 414]. While this is not surprising for a viral infection, uncontrolled inflammation can become detrimental causing neuroinflammation and neurocognitive impairments [415]. This is exemplified in mice overexpressing IFNα in the brain, which are both protected from viral encephalitis, but also develop progressive neurodegeneration as a consequence of persistent neuroinflammation [416]. Importantly, IFNAR signalling is required for neurocognitive decline and neuroinflammation due to HIV, in vivo [417, 418]. Recognition is thought to occur via stimulation of nucleic acid sensors TLR7 and TLR9 [419], IFI16 and STING [420], RIG-I [421], all converging on type I interferon production. This is paralleled in HIV infected individuals as IFNα is detectable in CSF [422] and correlating with viral load [423, 424] as well as NfL [425] providing further credence to the neurotoxic effect of sustained type I interferon production in brain following HIV infection.
Evidence also exists that while ART may inhibit viral replication, neuroinflammation remains unabated. In a brain organoid model, HIV infection leads to upregulation of type I interferon, interferon-signatures, and of other inflammatory mediators in microglia, the main infected cell in brain, causing elevated inflammatory outcomes also in non-microglial cells [426]. This further reflects the extent of damaging responses to HIV in cells not directly infected. Importantly, while ART causes ablation of the expression of HIV proteins, microglia become a persistent reservoir of HIV [405] exemplified by continuous production of interferon-response CXCL10 and chemokine CCL2 despite ART [426] suggesting that intracellular viral recognition and response sustain a replication-independent inflammatory response. Consolidating the observation that ART does not abolish HAND incidence is the fact that, while it suppresses viral replication, it does not affect latent virus [427]. This is reflected by the persistence of interferon-response gene expression in patients undergoing ART [413]. Hence, it is reasoned that the microglial viral reservoir alone may be sufficient to perpetuate neuroinflammation and HAND, even at low or undetectable viraemic loads. It is important to note that not all ART display the same CNS penetrance. The structure of the BBB coupled with organised efflux mechanisms block or severely limit the access of ART to this reservoir and argues for the development of new generation ART with improved brain penetrance [428, 429].
Beyond HIV, there may be parallels to other viral infections. Cognitive deficits have been recorded in patients recovering from COVID-19 following SARS-CoV-2 infection [430, 431, 432, 433]. The virus is known to infect the choroid plexus as viral entry factors including the receptor ACE2 are highly expressed by its epithelial cells [335, 434]. The interferon signatures [335] were found to parallel what is seen in neurodegenerative diseases [216, 217, 218, 219, 220, 221] as well as choroid plexus during ageing [267], lending to the hypothesis of a type I interferon-associated cognitive dysfunction pathway in COVID-19 [334].
Research on the rare type I interferonopathies, which typically present in infants, has been challenging. Case studies and small patient cohorts account for most of our knowledge of this family of diseases. Understanding the mechanisms by which type I interferon causes neurologic disease can have substantial impact on treatment of interferonopathies. Type I interferons are also implicated in other non-mendelian diseases which are often accompanied by a predominant neurological component. Therefore, a better mechanistic understanding could have important implications for more common neurological diseases. The following section describes some of the better-known effects in the brain, linking together different disorders and emerging concepts, and highlights some of the remaining open questions.
5.1 Local source of interferons in the brain
Type I interferons can be produced by almost every cell in the CNS, despite lacking dedicated – or “professional” – producers of these cytokines. Being most prominently produced in response to nucleic acids, expression patterns of nucleic acid sensors therefore dictate for the most part whether any specific cell type produces interferons. Some, basally express virtually all nucleic acid sensors, such as microglia, whereas others, such as astrocytes, express a more specialised subset of sensors.
Astrocytes have been proposed as a major producer and responder in AGS caused by TREX1 or RNASEH2 mutations [435, 436, 437]. Immunohistochemical staining of postmortem brain sections revealed that astrocytes were the main producers of IFNα and CXCL10, a typically interferon-responsive chemokine. Mutations in the genes associated with AGS cause aberrant accumulation of DNA which becomes the trigger for production in astrocytes [438, 439]. Moreover, chronic exposure to IFNα was found to cause aberrant activation of astrocytes making them reactive, while simultaneously inducing gene expression changes reminiscent of AGS [436].
Microglia are thought of as the main producer in more common neurodegenerative diseases. In Alzheimer’s disease, both Aβ oligomers [232, 247, ] and amyloid-associated nucleic acids [228, 229], as well as soluble tau [237, 239, 240, 440] are capable of triggering production from microglia. This is also the case for HIV-associated neurocognitive disorders, which is less surprising given that microglia are the main CNS reservoir for HIV [405].
Neurons and oligodendrocytes can also produce type I interferons, albeit to a lesser extent than astrocytes and microglia. They have been found to express TLR3 and to be capable of producing IFNβ in response to dsRNAs [441, 442]. Neurons also express cGAS-STING and respond to mtDNA by triggering the production of IFNβ [287]. They are also found to express TLR9 [443, 444], TLR8 [445], TLR7 [446, 447], RIG-I [448], though evidence of their involvement in production of interferons remains for now limited.
Brain vascular endothelial cells form an important direct interface between the brain parenchyma and the circulation. The cGAS-STING pathway plays an important role in vascular endothelial cells, as exemplified by the observation that mutations in the STING1 gene cause overt production of type I interferons leading to vasculopathy [449]. Brain endothelial cells produce type I interferons [282, 450] and they are known to be able to do so via STING [281, 451], via RIG-I [452, 453], or also in response to TNF through IRF1 [454]. While more research is needed on the endothelial cell contribution to type I interferon production specifically in the brain, convincing evidence exists that they are capable of it.
In addition to nucleic acid sensors, surface pattern recognition receptors are also expressed by cells in the brain. It is well-described that TLR2 and TLR4 respond to disparate triggers including viral proteins, protein aggregates, and bacterial lipids initiating production of pro-inflammatory cytokines. This includes type I interferons which are produced through TLR2-MyD88 and TLR4-TRIF [455, 456]. TLR2 and TLR4 are known to be expressed on microglia, astrocytes, and brain endothelial cells, and neurons are described to express TLR4. It is important to note that induction of type I interferons is also mediated through pathways other than nucleic acid sensing during neuroinflammation.
Direct evidence for type I interferon production in vivo is difficult to obtain. High, ubiquitous expression of the IFNAR causes low bioavailability of these cytokines, but also results in interferon-related signatures that are powerful surrogate markers. Despite this, technologies that allow the direct detection of IFNα and IFNβ have enabled the quantification of significant increases in the CSF of HAND, neurolupus, and AGS patients, suggesting high continuous CNS production. Ultimately, which cells in the CNS produce type I interferons is often context and disease dependent. Another important consideration is that some nucleic acid sensors can also be induced by type I interferons themselves, thereby initiating a chain reaction of production which can be self-sustained for as long as stimuli are present. In some cases, production is initiated in the periphery causing multiorgan diseases with sometimes prominent CNS involvement.
5.2 Systemic source of interferon
Interferons produce systemically are also capable of signalling to the brain [457]. In mice, it was demonstrated that delivery of systemic interferons stimulates the induction of interferon-response genes in brain parenchymal cells [458], and that microglia become strongly activated and to upregulate complement alongside classical pro-inflammatory interferon-responses [459].
The exact mechanisms by which peripheral type I interferons signal to the brain are not fully understood. From research on the cross-talk between peripheral inflammation and the CNS, it is reasoned this can happen in any of four different ways [460]: (1) passively across the BBB and through brain regions called circumventricular organs, which are devoid of a BBB and highly permeable to permit rapid communication between CNS and circulation [457, 458], (2) through induction of BBB leakiness via downregulation of adherens and tight junctions [166, 277, 450], (3) by active uptake through the choroid plexus endothelial cells [166, 267], or (4) through cell migration across the BBB, such as activated monocytes attracted to a microglial CCL2 gradient [361] which may carry type I interferon signalling. Though less is known about the latter mechanism, it is thought that this is a primary mechanism contributing to depression [460, 461, 462].
The most obvious example of systemic production of type I interferons is lupus. In SLE, plasmacytoid dendritic cells (pDCs) and monocytes are thought to be primary sources [463, 464, 465, 466, 467] however, despite being a systemic disease, it is difficult to posit that there is no production in the brain.
Type I interferons form an important innate immune defence barrier, and are, as such, capable of being produced by all cell types, depending on the inflammatory context. They can be produced in response to viral or bacterial infections, or in response to damage associated signals, either locally in the brain or systemically, and to freely traverse the BBB. It is probable that interferon production in both the circulation and the CNS concomitantly contribute to neuroinflammation, even when the source appears predominantly either systemic or central.
5.3 Cellular responses to interferon in the brain
While sources of interferon can be various, all type I interferon signalling converges through a single surface receptor, the IFNAR. This ubiquitously expressed dimeric receptor, formed of an IFNAR1 and an IFNAR2 chain, allows for a wide range of cellular responses, affecting various cell types. Microglia, astrocytes, neurons, and endothelial cells are known to respond strongly and in specific ways.
Microglia assume a hyper-ramified morphology [468], a typical change signifying activation and immune surveillance mechanisms. Microgliosis is strongly induced by type I interferons, and across neuroinflammation models, whether AD, AGS, or lupus, it is dependent on IFNAR signalling. Concurrently, increased processes and complexity are also induced, which typically signify increased synaptic pruning. Short-lived proliferation and apoptosis following long-term stimulation are also observed. Lastly, their antigen presentation capacities are enhanced by upregulation of MHC I and II genes and of activation markers CD68, CD40, CD80, and CD86 [228, 459, 468, 469, 470]. This is further exemplified in single cell studies across human AD and mouse models, where interferon-response signatures overlap with antigen processing and presentation genes.
Astrocytes also respond to type I interferons, though their interferon-response gene expression is less pronounced than that of microglia [469]. It also seems that, in AD models, astrocytosis is not dependent on interferons. This is in contrast to AGS, where astrocytes are thought of as the primary involved cell type [436]. Intriguingly, like microglia, they also upregulate genes related to the antigen presentation machinery, though they are not classically thought of as APCs. Yet, reactive astrocytes display antigen presentation characteristics, as well as astrocytic toxicity markers.
Endothelial cells of the brain vasculature are major responders to type I interferons. They respond by producing chemokines, allowing cell infiltration, and succumbing to apoptosis leading to vascular dysfunction. An AGS mouse model driven by astrocyte promoter-dependent production of IFNα recapitulates microangiopathy, perivascular T-cell infiltration, perivascular calcification, and capillary calibre and formation of aneurysms seen in human patients [44]. Importantly, endothelial cell-specific ablation of IFNAR causes near-complete rescue of cerebral vascular disease [44], suggesting that endothelial cells are the principal responders in AGS and a major target for type I interferon-driven neuroinflammation. Endothelial cells exposed to type I interferons display reduced mobility and invasion [471], in line with their cancer inhibiting properties [472]. In fact, IFNAR signalling inhibits vascular endothelial cell growth factor (VEGF)-induced proliferation [452] highlighting the anti-angiogenic potency of these cytokines. It was shown that CXCL10 can inhibit endothelial cell proliferation in a CXCR3-dependent [473] and -independent [474] pathway. Interferon-inducible IFI35 is also described as an important inhibitor of endothelial cell proliferation and migration [475], indicating that multiple parallel pathways exist. Further accentuating the importance of type I interferons in endothelial cell biology is the surprising discovery of basal interferon-response expressing endothelial cells across different organs including the brain [476] suggesting a regulatory and homeostatic role of tonic type I interferon signalling, though research is needed to characterise these cells and their roles.
5.4 Immune cell infiltration
Certain chemokines such as CXCL9, CXCL10, and CXCL11 are known to be preferentially interferon-inducible, while others, such as CCL2, CCL5, and CCL20, are also induced by interferons but not exclusively. While microglia also display important chemokine production in response to interferons, vascular endothelial cells are particularly suited to the task by virtue of their position at the interface between tissue and circulation. Chemokine gradients and presentation at the lumen side allows for efficient recruitment of immune cells expressing cognate chemokine receptors. In brain endothelial cells, IFNβ treatment causes upregulation and production of CXCL9, -10, -11, CCL2, and -5 which are also able to signal in the brain parenchyma [166]. They bind CXCR3, CCR2, and CCR5 which are predominantly expressed on T-cells, NK cells, monocytes, and dendritic cells, among others.
It has been reported that IFNβ can also inhibit monocyte infiltration by downregulation of adhesion molecules during experimental autoimmune encephalomyelitis (EAE) [477], a model of MS, supporting the anti-inflammatory characteristics observed in MS. It is unclear whether this is disease- or tissue-context specific, as subcutaneous administration of IFNβ in MS patients causes upregulation of the aforementioned chemokines accompanied by extensive T-cell and macrophage perivascular infiltrates [478]. IFNα overexpressing mice show extensive perivascular infiltrates in the brain [416, 479] which depend specifically on endothelial cell IFNAR signalling [44]. Despite having elevated interferon-responses, ADAR1 mutation-carrying mice do not, display perivascular infiltrates [480], while a different nuclease deficiency, RNASET2, leads to IFNAR-driven T-cell and monocyte infiltration [481]. In the context of brain injury, IFNAR-signalling enhances T-cell and monocyte recruitment [382]. This suggests that type I interferon-driven immune cell infiltration is context dependent and requires more research to fully elucidate the underlying differences that set the final outcomes apart.
5.5 Vascular dysfunction
As a consequence of inhibition of normal endothelial cell proliferation and function, it is not surprising that type I interferons can also cause pathogenic vascular dysfunction. IFNAR signalling in endothelial cells specifically causes development of BBB disruption, microangiopathy, calcification, neuron loss and premature death in an AGS mouse model [45]. There is also clinical evidence supporting this observation. Exogenous interferon therapy has been associated with thrombotic microangiopathy in a dose dependent manner [168, 482]. Type I interferons cause abnormal brain vascular morphology, displaying smaller size microvasculature, sections of widened vessel formation, and microaneurysms. Specifically, vascular lumen narrowing is seen diffusely across the brain [168]. The interferon-inducible IFITM1 protein has been discovered to be implicated in the formation of stable vascular lumen during angiogenesis through stabilisation of endothelial cell-to-cell interactions [483]. While loss of IFITM1 leads to abnormal vessel formation, it is for now unknown whether upregulation can also disturb endothelial cell-to-cell contacts resulting in inappropriate vascular lumen formation and dysfunction.
Certain contexts, such as viral infection, can greatly inhibit normal function and healing until viral stimuli are cleared. In endothelial cells, it is found that viral sensing through MDA-5 triggers IFNβ production. This thereby blocks vascular repair, angiogenesis, and BBB restoration following injury, causing a failure to recover normal neurological function [280, 484]. It is likely that even milder neurovascular damage, in the presence of overactive interferon signalling, can cause similar outcomes. In a mouse model of AD, IFNβ correlates with BBB disruption and contributes to it by downregulating adherens junctions and tight junctions causing leakiness [277]. Both IFNβ and IFNAR1 expression is markedly increased in vascular endothelial cells in vivo compared to non-AD-prone mice, indicating an induced hyper-sensitivity to type I interferons which is likely caused in some form by amyloids. While Aβ can trigger microglia to produce type I interferons by multiple mechanisms, it is unknown whether similar mechanisms take place in endothelial cells. Importantly, upregulation of IFNAR can be a key sensitisation step that needs further research. Cerebral amyloid angiopathy (CAA) is a condition where amyloids deposit along the walls of cerebral blood vessels [485]. This causes microhaemorrhaging which further precipitates cognitive decline [486, 487]. Furthermore, current generation anti-amyloid therapies are known to cause amyloid-related imaging abnormalities (ARIA), essentially aggravated haemorrhaging induced by the amyloid targeting therapies. It is for now unknown whether there is a direct link between CAA and type I interferon signalling, and whether they participate in the induction of ARIA.
Following BBB disruption, leakage of blood products containing DAMPs of various sources gain access to the brain parenchyma and trigger damage sensors. One such activator is fibrin, a powerful trigger of CD11b/CD18 surface heterodimers expressed on microglia and which is gaining emerging interest as the full extent of its involvement in CNS diseases and neurodegeneration [488]. During AD progression, mice lacking fibrinogen, a plasma protein required to create fibrin, show reduced gliosis, neuronal damage and cognitive decline and suggest that vascular damage synergises with amyloid pathology [489]. The type I interferon pathway is found to be strongly triggered by fibrin [490] indicating that a leaky BBB can also directly trigger this neuroinflammatory pathway and suggesting a self-sustained feedforward mechanism of interferon-BBB leakage-interferon. The exact trigger for type I interferon production, whether indirect or direct, remains to be elucidated – whether indirectly through induction of DNA release following mitochondrial or cell damage, or directly through a potentially novel pathway. Yet, if not properly regulated, this is likely a mechanism through which neurodegeneration-inducing neuroinflammatory events can propagate throughout the brain.
As for how exactly type I interferons cause calcifying microangiopathy, this is still an open question. One hypothesis is that subclinical disruption of microvessels may be sufficient to cause continuous deposition of calcium along vessel walls. Evidence of direct induction of calcification also exists in vitro, as IFNα precipitates calcification at concentrations in the range found in CSF patients [491]. Finally, it is thought that cell senescence is linked to calcification, but it is unclear which one causes the other and how [41]. While type I interferons are known to cause both calcification and cell senescence, it remains to be discovered how this mechanism is mediated and whether through senescence.
5.6 Phagocytosis and synaptic pruning
Overall, type I interferons have been found to both inhibit appropriate microglial removal of aggregated proteins and debris, but also to enhance synaptic engulfment and neuronal elimination.
While in the context of AD it is still debated whether amyloid plaque formation is truly detrimental by enhancing neuronal network disruption or whether it renders reactive amyloid peptides unreactive in extracellular clumps, amyloid plaque deposition is generally accepted as a sign of exhausted phagocytosis. In vitro, both IFNα and IFNβ significantly reduce phagocytosis in a dose-dependent manner [262]. Furthermore, IFNAR signalling interferes with normal Aβ phagocytosis. This coincides with an increased pro-inflammatory state including increased cytokine production. This suggests that type I interferon drives mitochondria away from a phagocytic clean-up function towards a hyper-reactive pro-inflammatory state.
In vivo, there are some contradictory results, however [229, 262]. In APP/PS1 mice, plaque deposition seems grossly unaltered [262] whereas a different group could demonstrate decreased plaques [229]. Importantly, this was observed in mice lacking IFNAR specifically in non-microglial cells, but not in mice lacking microglial IFNAR. This seems to suggest that the phagocytic activity against plaques in microglia may be driven by unalterable genetic drivers which can, at best, be modulated by changes in neuronal interferon-inducible IFITM3. Likely, these results do not rule out clearance of reactive oligomeric amyloids, which may act by decreasing the overall inflammatory state. These results cannot rule out a possible effect in human LOAD where genetic drivers for amyloid deposition should be other than aberrant processing of amyloids.
Complicating matters further is the observation that type I interferons upregulate phagocytic markers [492] and promote synaptic pruning leading to neurodegeneration [228, 229, 233, 249, 352, 493]. Synapses are specialised junctions through which neurons signal to each other. They consist of three parts: the presynaptic terminal of the signalling neuron, the synaptic cleft, and the postsynaptic terminal of the target cell. Synaptophysin is a membrane glycoprotein present in presynaptic vesicles and is involved in the regulation of neurotransmitter release. Postsynaptic density protein 95 (PSD-95) is a scaffolding protein located in the postsynaptic density of excitatory synapses and it plays a critical role in anchoring and clustering neurotransmitter receptors and other signalling complexes at the synaptic membrane. Synaptic pruning mechanisms occur via phagocytic microglia and astrocytes in a complement-dependent mechanism [494, 495]. During synaptic pruning, certain synapses are tagged for removal by complement proteins such as C1q and C3. These proteins bind to the synapses and mark them for elimination. Microglia express complement receptors that recognise these tagged synapses. Once bound, microglia can engulf and digest the synaptic material, effectively pruning the synapse. This mechanism ensures the refinement of neural circuits and is essential for proper brain development and function. Dysregulation of this process leads, however, to neurodegenerative diseases. Type I interferons are found to induce complement-dependent synaptic pruning across multiple neurodegeneration models, but also in normal healthy development [496, 497] suggesting that this is a conserved mechanism and that it requires delicate regulation. Inducing the expression of complement components, such as C1q, C3, and C4, to mark synapses for elimination is perhaps only part of the mechanism, and it is still unclear whether interferons can also enhance the activity of complement receptors binding to complement-opsonized synapses, such as CR3 and CR4, and facilitate their engulfment.
Overall, type I interferons activate microglia to become reactive and pro-inflammatory, and to poise them for complement-driven synaptic pruning and neuronal engulfment, while rendering them unable to clean up reactive aggregated proteins. Whether this is a result of task overload, or a preferential outcome due to a switch in signalling remains to be determined and the underlying mechanisms discovered.
TBI is perhaps the most typical display of neuroinflammation features [498, 499, 500] which are associated with development of dementia [501, 502]. The neurodegeneration process persists long after the concussive event where reactive microglia morphology and upregulation of CD68 can be observed years after injury along with white matter atrophy [503]. Single nuclei RNA sequencing reveals an interferon signature in oligodendrocytes [377], the specialised glial cell type forming the myelin sheath typical of the white matter and allowing the efficacious saltatory nerve conduction between neurons.
These observations have been corroborated in bona fide mouse models of TBI which have been used to expand on the mechanistic link between brain injury, type I interferon signalling, reactive microglia, and neurodegeneration. Sustained type I interferon signatures are found strongly upregulated during TBI in both microglia and astrocytes, alongside genes related to glial reactivity [374]. Reactive microglia morphology and CD68 expression were also found to be induced by type I interferons directly in vivo [228]. Importantly, inactivation of IFNAR leads to reduced neuronal loss and protection of white matter resulting in improved neurocognitive function [382, 383]. STING-deficient animals lose most of the type I interferon signatures [385], hence the trigger itself can be speculated to be massive release of nucleic acids from damaged cells. Remarkably, neuronal STING-derived IFNβ alone is sufficient for promoting neuroinflammation [384, 395], in part through a decrease in NOX2, an important inflammatory mediator of post-traumatic neurodegeneration [396, 398]. IFNβ also initiates a CXCL10-driven white matter injury process, through CXCR3-dependent and -independent neurotoxic activities, and through induction of Th1 cell infiltration [395]. Yet, this does not account for the sustained interferon production succeeding acute trauma. Perhaps type I interferons cause a feed-forward loop of aberrant neuronal engulfment as explored in the previous section: nucleic acid sensing, accrued interferon production, more neuronal engulfment – rinse and repeat. While this remains to be demonstrated, an immune cell infiltration feed-forward loop exists which explains the self-sustained pathogenic interferon signatures [362, 378]. Monocytes in the meninges are found to produce CCL2 and to strongly upregulate interferon signatures [378]. That causes a CCR2-dependent recruitment process which is also remarkably required to propagate the type I interferon signatures during TBI [362], thus together suggesting a feed-forward loop of unabated interferon-response and immune cell infiltration.
Type I interferon initiates a potent neuroinflammatory response to brain injury, causing direct neuron and oligodendrocyte damage, and instigating monocyte and T-cell infiltration that potentiates and prolongs detrimental responses. The mechanisms identified validate targeting type I interferon or its downstream effectors as a therapeutic strategy in TBI. Inhibiting type I interferons leads to an ordered conclusion of the self-sustained inflammatory process, thereby promoting favourable neurocognitive outcomes.
Put together, the mechanisms by which type I interferons are known to affect the brain are numerous and act by perturbing multiple key processes required for neuronal function. From promoting neurodegeneration, to causing microangiopathy, to precipitating premature ageing, to promoting depressive states, type I interferons are an important neuroinflammatory target (Figure 3).
Figure 3.
Putative mechanisms of concerted psychocognitive disturbance by pathogenic type I interferon dysregulation. Neurodegeneration in the context of Alzheimer’s disease-related proteinopathies implicates type I interferon at multiple levels. DNA associated with amyloid plaques triggers the production of type I interferons by microglia, which become reactive in response to paracrine IFNAR signalling [228, 229]. Activation of IFNAR signalling in microglia causes upregulation of DNA sensors amplifying the response and promoting self-sustained activation [266]. CXCL10, produced in response to type I interferons, signals to CXCR3-expressing neuronal presynaptic terminals. This causes hyperexcitability and initiates chronic responses, leading to the impairment of new memory formation [286, 288, 504]. Interferon also activates complement driven neuronal synapse pruning by astrocytes contributing to loss of existing memory networks and cognitive decline [228, 229, 352]. They also induce direct effects on neurons. Neurons upregulate IFITM3, which enhances γ-secretase activity, increasing APP processing, and Aβ production [229, 275]. Aβ triggers type I interferon production by microglia [228] and neurons [247] while contributing to amyloid plaque formation when coupled with interferon-induced defective phagocytosis from microglia [262]. MEF2C, a cognitive resilience transcription factor, is downregulated in microglia and neurons. This leads to dysfunctional pro-inflammatory responses in microglia and the initiation of a premature cell senescence programme, promoting neuronal loss [233, 249, 268]. Interferons trigger mitochondrial destabilisation in neurons, contributing to neuronal cell death [263, 264, 265] and through concurrent activation of upregulated nucleic acid sensors [266] and mitochondrial DNA release, they cause neuronal type I interferon production [505, 506, 507]. Signalling to oligodendrocytes [239] leads to as yet undefined consequences, and in neurons promotes neuronal tau hyperphosphorylation and seeded aggregation [237] further contributing to the neurodegeneration process. Type I interferons also contribute to significant changes in the blood-brain barrier. Endothelial cells respond to type I interferons by producing chemokines CCL2 and CXCL10 which mediate perivascular immune cell infiltration [166, 168, 171, 294, 295, 296]. Recruited immune cells are activated by interferons to upregulate ROS via NOX2 and IDO1, contributing to neuronal and BBB damage [156, 384, 387, 396, 397, 398, 399, 401]. Vascular endothelial cells from the BBB are concurrently activated by IFNAR-induced mediators CXCL10 and CCL2 to downregulate adherens and tight junctions, resulting in a leaky barrier and promoting microangiopathy [279, 280, 281, 282, 300]. The mechanism by which type I interferons cause calcification of vessels in the systemic circulation and basal ganglia is unknown, but it is thought to be related to premature ageing. MEF2-family of transcription factors are gatekeepers of cellular senescence. Cognitive resilience-associated MEF2C is downregulated by IFNAR signalling, precipitating loss of endogenous retroviral element regulators such as TREX1, thereby inducing aberrant triggering of nucleic acid sensors and leading to self-amplified type I interferon production associated with the senescence-associated secretory phenotype (SASP) [258, 268, 348, 349, 350, 351, 352] as is the loss of MEF2A which also causes unabated IFNβ production through increased DNA:RNA hybrid accumulation [508]. Type I interferon-induced CCL2 and CCL11 are thought to be linked to induction of cell senescence [166, 171, 359, 360, 361, 362] though the exact mechanisms remain to be fully elucidated. Finally, inhibition of NRF2 by IFNAR signalling leads to increased ROS which exacerbates the inflammaging process [339, 340, 341]. Put together, these mechanisms are responsible for ageing-related cognitive decline. These outcomes are overly apparent at the choroid plexus and likely take place diffusely across the brain parenchyma. Type I interferon is also well known to be an inducer of depression through metabolite, inflammatory, and hormonal mechanisms. IDO is induced in response to interferon and perturbs the balance between the excitotoxic quinolinic acid metabolite and the neuron protective kynurenic acid and serotonin, causing excessive NMDAR agonism [104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 156]. Cyclooxygenase inhibition via NSAIDs also attenuates IFNα-induced depression through undescribed mechanisms [173]. Concurrently, the interferon-inducible CXCL10 is also known to lead to weakened synaptic long-term potentiation in the hippocampus, resulting in a depressive phenotype [166, 171]. It remains to be elucidated whether the protective effects of COX1, -2, and PLA2 inhibition are acting through inhibition of the interferon-induced synaptic CXCL10-CXCR3 signalling. Together, all these mechanisms likely act in concert to cause the detrimental neuropsychiatric effects caused by type I interferons.
There are numerous existing approaches for targeting type I interferons and their downstream signalling, with great therapeutic application potential.
6.1 Targeting the receptor
The entire type I interferon pathway is dependent on a single juncture point, the IFNAR. This effectively acts as a central hub controlling all its downstream signalling. The advantage of targeting IFNAR over individually targeting any of its 13 IFNα subtypes, IFNβ, IFNε, IFNκ or IFNω, or combinations thereof, is evident. The generation of a mouse anti-IFNAR1 blocking monoclonal antibody [509] was a turning point for the field and for the pharmaceutical industry, both by facilitating research in vivo and elucidating the role of the pathway outside of genetic manipulation, and by providing a surrogate for the potential of therapeutic targeting in human. A fully human monoclonal IgG1κ antibody targets IFNAR1 with high affinity and specificity, neutralising its receptor activity [510]. Anifrolumab is now approved in most countries for the treatment of SLE following breakthrough improvement in disease scores, higher rate of achievement of remission, high retention rate and low immunogenicity and side effects [92, 93, 511, 512, 513, 514]. It is important to note that the percentage of herpes zoster reactivation was increased by anifrolumab compared to placebo, surprisingly no other notable adverse events were seen up to 3-years after treatment initiation [512, 515]. Furthermore, an indirect analysis of results from the TULIP-1 and TULIP-2 phase III trials of anifrolumab, and BLISS-52 and BLISS-76 trials, two phase III trials randomised, double-blind, placebo-controlled tials of belimumab, an anti-BAFF monoclonal antibody, reveals that treatment with anifrolumab was associated with significantly greater benefits [516]. Belimumab had been a revolution in the treatment of SLE [517, 518], and is the only other and first approved biologic for SLE. Its potent B-cell survival inhibitory effect is being leveraged in combination therapies with tacrolimus [519] and rituximab [520, 521]. While no head-to-head comparisons have been made between anifrolumab and belimumab, warranting caution on conclusions drawn, anifrolumab far exceeds the efficacy outlook for the current approved treatment landscape for SLE. That includes sifalimumab and rontalizumab, two anti-IFNα monoclonal antibodies, which have shown efficacy and good tolerability profiles [90, 522, 523, 524], but which lack the broad efficacy achieved by the complete blockade of type I interferon signalling.
The approval of anifrolumab, only the second biologic for lupus, reinvigorated the field and validated a long-known central role of type I interferons in SLE. This created excitement beyond the lupus field, as trials are being conducted for other indications including for Rheumatoid Arthritis (NCT03435601), Primary Sjögren’s Syndrome (NCT05383677), Systemic Sclerosis (NCT05925803), Progressive Vitiligo (NCT05917561), and Hidradenitis Suppurativa (NCT06374212). Regarding monogenic type I interferonopathies, as of yet, only one single patient carrying a DNASE2 mutation has received anifrolumab, with remarkable amelioration [525]. While neurological involvement is frequent in DNASE2 loss-of-function interferonopathies, this patient had normal neurologic status at the time of their treatment, thus it is not known whether this approach may be useful for treating psychocognitive symptoms.
6.2 JAK inhibitors
Inhibitors targeting the JAK/STAT signalling pathway have shown efficacy and promising results in various diseases. JAK inhibitors like tofacitinib, filgotinib, and upadacitinib have been approved for use in multiple disorders, modifying treatment algorithms across a range of disease states, including myeloproliferative neoplasms, rheumatoid arthritis, and various inflammatory dermatological disorders. The rapid and broad bench-to-bedside translation is a testament to the importance of this pathway to different disease mechanisms. For neurological diseases, however, there has been slower adoption, despite promising preclinical results. Notably, inhibition of JAK/STAT signalling in mouse models of DS resulted in attenuated interferon-response signatures [307]. Dp16 mice, which harbour a duplication of murine chromosome 16 and which is orthologous to human chromosome 21, show upregulation of inflammatory and interferon responses in brain, along with other tissues [307]. Treatment with the JAK1/2 inhibitor baricitinib caused attenuation of many dysregulated signatures of Dp16, including of interferon-response genes, and including in the brain. Importantly, a patient treated with tofacitinib for an underlying alopecia areata [526] displayed marked inhibition of interferon-response signatures in the circulation to levels similar to euploid and healthy individuals, including abrogation of the major signalling chemokines CXCL9 and CXCL10 [307]. Beyond neuroinflammation due to genomic aberrations specifically associated with DS, JAK/STAT signalling inhibition using ruxolitinib was also capable of inhibiting type I interferon-driven neurodegeneration in a model of ALS-FTD [527]. Specifically, C9orf72-mutation associated FTD and ALS are found to accumulate cytoplasmic dsRNAs which trigger production of type I interferons, and culminate in JAK/STAT-mediated neuronal cell death. Proof-of-concept evidence exists that the interferonopathy in DS and nucleic acid accumulation in FTD and ALS can be modulated pharmacologically by JAK/STAT inhibitors, and taken together with the mouse model assessments suggests that neurocognitive protection may be possible.
There are still questions about the efficacy of JAK/STAT inhibition for neurological disease. In both AGS [528, 529, 530, 531, 532], SPENCD [533], and SAVI [530] JAK1/2 inhibitors caused systemic amelioration of dermatologic or pulmonary disease, including of systemic type I interferon signatures, but neurological improvement was limited or absent. Frequent infections are also seen, as essentially all cytokine signalling is inhibited, and is an important consideration especially for paediatric patients lacking fully developed adaptive immunity relying on innate immunity. Often, this has led to transient discontinuation of therapy, which may have impacted outcomes. This suggests that targeted therapy, particularly one specifically targeting type I interferons, may be more efficacious. A handful of case studies have reported better success for neurologic signs in AGS [534, 535, 536], of which one demonstrated reduced type I interferon in CSF for one patient [534], arguing perhaps in favour of early and uninterrupted therapy. Assessment of CSF exposure of the inhibitors reveals levels below 10% that of plasma, which is reflected by poor biomarker responses in CSF compared to circulation [531] indicating a need for brain penetrant molecules for consistent responses.
6.3 Experimental therapeutic approaches
Few other interferon-targeting treatment approaches exist, and most remain for now experimental. Reverse-transcriptase inhibitors were found to strongly inhibit interferon-responses in circulation and in CSF in AGS [537]. It is thought that repressing expression of otherwise uncontrolled endogenous retroelements may be sufficient to regulate type I interferons, but perhaps not all patients may benefit similarly. These changes were most efficacious in patients carrying mutations in components of the RNASEH2 complex, and signatures were reversed upon discontinuation indicating specificity of the signal to the treatment. It is unclear if this treatment approach could be used for lasting responses with favourable clinical outcome, especially in the brain. It is also difficult to extrapolate from the clinical course of HAND where, despite anti-retroviral therapy, neurocognitive deterioration continues, as pathological mechanisms are different. Interestingly, trials are being conducted in Alzheimer’s disease (NCT04552795) which may yield better understanding of how retroelements are implicated in neuroinflammation [538].
Synthetic nucleotides for gene silencing are being intensely researched for drug development [539]. Antisense oligonucleotides (ASOs) hybridise cellular RNA and modulate processing, splicing, cause competitive inhibition, block the translational machinery, or degrade the bound target mRNAs. Treatments based on ASOs have already reached the clinic for genetic disorders such as Duchenne muscular dystrophy [540] and SOD1 mutation-associated ALS [541]. In a type I interferonopathy mouse model, intrathecal delivery of ASOs targeting the Ifnar1 gene rescued neuropathological phenotypes by reducing type I interferon-responses, which led to reduced gliosis, immune cell infiltration in brain, reduced neuronal death and tissue destruction, and prevention of BBB leakage [542]. Such an approach lends itself well to monogenic type I interferonopathies and, coupled with a rationale-driven administration method, may benefit patients based on their personalised symptomatology.
Type I interferons are cytokines that play a crucial role in the innate immune response against viral infections and in anti-tumour activities within the CNS. Overactivity of this pathway, however, results in aberrant responses that cause neurodegeneration. Concrete examples of this are persistent viral infections of the brain causing HAND, neurocognitive symptoms in archetypically type I interferon-driven diseases such as SLE and AGS, and the profound psychocognitive effects of therapies with IFNα and IFNβ. Type I interferons are also found aberrantly overexpressed in more common diseases such as major depression, AD and dementia attributed to TBI, DS, and ageing, giving rise to the hypothesis that they may be detrimental more widely across neurodegeneration. With compelling evidence from preclinical models in all aforementioned disorders, there is interest in further developing therapeutics that target this pathway.
This also has implications for current clinical practice. The historical significance, extensive clinical experience, and diverse applications of IFNα and IFNβ therapies contribute to their sustained use in treatment practices. These once pioneering biologics remain relevant due to their foundational role in immunology and their proven benefits in some clinical indications. However, their long-lasting effects on the brain are an important consideration, and perhaps even more so due to their seeming implication in natural and disease-associated cognitive decline.
7.2 Limitations, challenges, and open questions
Open questions remain on the therapeutic potential of targeting type I interferon signalling for neurological disorders. SLE, a disease caused by systemic type I interferons, leads to neuropsychiatric symptoms, including depression, in a substantial proportion of patients, mirroring exogenous therapy with IFNα or IFNβ. It will therefore be important to evaluate if blockade of type I interferon signalling affects neuropsychiatric outcomes in lupus. The most direct evidence for this may come with the now marketed IFNAR1-targeting anifrolumab. Though trials performed to date were not powered for addressing this, long-term follow-up and more extensive clinical experience should clarify this. Also, it is unclear whether targeting the IFNAR systemically will be sufficient to influence the CNS. This may depend on the CNS-penetrance of anifrolumab, which has not been evaluated. Typical CNS penetrance of antibodies is 0.1%, so for a dose of 300 mg it may be conceivable that sufficient antibody reaches the brain parenchyma, but not necessarily that sufficient target is neutralised. High, ubiquitous, target expression explains a short half-life of the antibody, meaning lower amounts of free antibody capable of reaching the brain. PK/PD relationship studies from the TULIP-1 trial reveal that only the 300 mg dosing schedule allowed for approximately IC90 inhibition of interferon-response [513]. The lower dose group receiving 150 mg had sub-optimal or no inhibition of the systemic 21-IFNGS when the C average concentration in plasma was below 11.5 μg/mL, and at least 32 μg/mL plasma exposure was necessary to consistently and durably achieve IC90 [513]. This indicates that the current 300 mg IV Q4W regimen, while sufficient to block type I interferon signalling in circulation, may not be sufficient to achieve an effect in brain, and higher doses may be needed. Importantly, this problem applies to all neurologic and neurodegenerative diseases caused by type I interferons, so it remains to be determined whether anifrolumab in its current format may be sufficient to treat type I interferonopathies, AD, TBI, or depression.
Delivery of antibodies across the BBB is a hot research topic and remains a current challenge. Brain shuttling technologies are being developed [543], and higher brain penetrance is being achieved by adding shuttle peptides [544], receptor-mediated transcytosis mechanisms [545], and exosome [546] or viral [547] vector-mediated expression. Developing brain-penetrant IFNAR-inhibiting therapeutic compounds may be required to achieve neuropsychiatric or neurodegenerative improvement in type I interferon-driven diseases. Small molecules targeting upstream or downstream elements of the type I interferon pathway exist, and may be easier to be made brain penetrant.
Achieving clinical efficacy for neurologic disorders often requires long trials because of the inherent complexity of the nervous system and length of disease progression. Trials with anifrolumab have confirmed the importance of the type I interferon pathway in viral defence. Thus, further safety considerations may need to be addressed by future type I interferon-directed therapies, especially if made brain-targeting. Herpes zoster screening and patient selection may be needed to stave off serious adverse events, particularly in long trials. From a personalised medicine perspective, it may also become important to evaluate whether wider viral screening could inform response rates and side effects, as other immunological mechanisms may take over antiviral function.
In recent years there has been enormous advance in the use of neurological biomarkers, particularly NfL, following regulatory approval by the FDA as a surrogate marker of neurodegeneration in ALS [548, 549]. Unsurprisingly, the number of clinical trials of CNS diseases utilising this biomarker has been steadily increasing [548]. Broadened clinical use may also give further clues about the relationship with type I interferons and whether interferon-targeting therapies lead to any meaningful change in plasma or CSF NfL. NfL has already been shown to be correlated with IFNα in HAND [425]. It is unknown whether type I interferonopathies – archetypical neuroinflammatory diseases – display NfL release in plasma or CSF. This assessment could allow a better understanding of the mechanisms of neurodegeneration in a purely type I interferon-driven group of diseases In SLE, a disease characterised by systemic type I interferons, elevated NfL levels, particularly in patients with neuropsychiatric symptoms [83, 84, 86], may correlate with CSF or plasma IFNα or interferon-response signatures. As neuropsychiatric amelioration has for the most part not correlated well with general disease response, another interesting metric will be the assessment of NfL during therapy, and especially with the IFNAR pathway targeting therapies.
An important current consideration is whether it will be feasible to move away entirely from IFNα and IFNβ therapies. For MS, emerging treatments are proving to be more effective than IFNβ therapy, indicating a potential shift in therapeutic approaches [550]. In the context of chronic HCV, patients report better quality of life with oral antivirals than antivirals plus IFNα [551]. Newer generation antivirals may slowly phase out the need for interferons in viral infection [182, 183]. For cancer, new interest in the tumour microenvironment has created excitement leading to reticence in phasing out interferons from clinical care [552]. Some use may still remain for exogenous interferon therapies, particularly for high-risk patients in low-survivable diseases [553] where long-term neurocognitive effects may be less relevant or managed for the survival duration. Nevertheless, checkpoint blockade inhibitors [184], and immunomodulating therapies [155, 185] have allowed for advances in our understanding of cancer biology, and the creation of new classes of therapeutics.
Rare diseases can often inform findings relevant to more common diseases. Neurologic disorders are no exception. A prominent example is the role that early onset familial Alzheimer’s disease, a very rare monogenic form of Alzheimer’s, has had on shaping the understanding of sporadic disease. Perhaps the most important open question is whether our understanding of these relatively newly discovered type I interferonopathies may help develop therapeutics for more common, or equally devastating, neurologic diseases.
The author wishes to acknowledge the helpful editing, discussion, and scientific literature knowledge and contributions of Dr. Morgan Le Roux-Bourdieu and Rosaria Luongo. The author apologises for not being able to include the many other important articles that have contributed to the development of the type I interferon field.
A.M. is a full-time employee of AC Immune SA, a for-profit clinical-stage biotech. Other than salary, A.M. holds no equity, shares or financial conflicts of interest to disclose. The views expressed in this chapter are solely those of the author and the company had no role in the writing or editing of this chapter. At the time of writing, AC Immune SA is not pursuing any commercial interests related to interferons or their clinical use.
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Written By
Alessio Mylonas
Submitted: 13 June 2024Reviewed: 24 June 2024Published: 31 July 2024
Open access peer-reviewed chapter - ONLINE FIRST
