Hilal Bhat Karl S. Lang Cornelia Hardt Judith Lang
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Key Words
Interferon • brain • CNS • homeostasis • virus in brain • developing brain • brain inflammation • blood-brain-barrier • cognitive and psychological functions and degeneration
Abstract
While the role of interferon during systemic disease is well known and its immune modulating functions and its role in antiviral activity were extensively studied, the role of IFN-I in the brain is less clear. Here we summarize the most important literature on IFN in homeostasis of the CNS and induction of an IFN response during viral infection in the brain. Furthermore, we present work on the roles of IFN in the developing brain as well as during inflammation in the brain. Lastly, we aim to enlighten the functions of IFN on the blood-brain barrier as well as circulation and in cognitive and psychological functions and degeneration. In short, CNS astrocytes produce IFN-β, which is of high relevance for homeostasis in the brain. IFN-β regulates phagocytic removal of myelin debris by microglia. IFN-I limits the permeability of the blood-brain barrier. Disruption of the blood-brain barrier facilitates entrance of peripheral lymphocytes and inflammation. Viral infections during vulnerable phases of embryonic development cause severe fetal pathology and debilitating impairments to human infants. The roles of IFN in these scenarios are diverse and include deficits due to overproduction of IFN during the developmental stage of the brain as seems to be the case in pseudo-TORCH2.
Introduction
Interferons: Interferons are cytokines, which play an essential role in the anti-pathogenic control and immune modulation. Interferons are separated in three groups, type I, type II and type III interferons. Type III interferon (IFN-λ, IL-28/29), is an essential component of the innate immune response. It plays an important role in the antiviral, antifungal and antiprotozoal defenses in the mucosa [1, 2]. Genome wide association screens revealed an important role of IFN-λ in the control of hepatitis C virus [3]. Type II interferon is defined of Interferon gamma (IFN-γ), a cytokine, which acts mainly on specialized immune cells (i.e. macrophages). Type I interferons (IFN-I: α, β, δ, ε, ζ, κ, ν, τ, ω) are a group of different IFN-α genes and the IFN-b gene. Although they all bind to the same receptor, IFN-α receptor chain 1 (IFNAR1), the induced signal can be very different depending on the kinetic and affinity of the different Interferon-α subtypes [4]. The major function of IFN-I is the direct antiviral activity against a broad range of viruses [5]. Beside this, IFN-I is an important activator of the innate and adaptive immune system. However, IFN-I can also induce inhibitory signals (i.e. IL-10 and PD-1L) and thereby dampen the immune activation [6].
Interferon induction: Upon viral infections, usually a type I interferon (IFN-I) response is induced. Pattern recognition receptors (PRRs) located at the cell surface, in the cytoplasm and in the endosomes recognize foreign nucleic acids and non-nucleic-acid pathogen-associated molecular patterns (PAMPs). Most important inducers of IFN-I are Toll like receptors 3, 4, 7, 8, and 9, and the cytosolic PRR, MDA-5, Cardif and cGAS [7-9]. A complex network of downstream signaling molecules including the transcription factors of the IFN regulatory factor (IRF) family leads to transcription of IFN-α and IFN-β. They bind to the cytosolic IFNAR receptor and cause transcription of IFN-stimulated genes (ISG), thereby limiting viral life cycle in infected cells and causing an anti-viral state in bystander cells [10].
Antiviral activity: Almost all nucleated cells can respond to IFN-I. Upon IFN-I signaling several antivirally active genes are induced. One of the first active ISGs is the myxovirus resistance (Mx) protein, targeting incoming capsids prior to replication in case of Mx1 or preventing nuclear entry of HIV-1 in case of Mx2, both ultimately causing nucleocapsid degradation [11]. Active at the stage of viral translation, 2, 5-oligoadenylate synthetase (OAS) activates RNase L, which degrades viral RNA [12, 13]. Proteinkinase R (PKR) phosphorylates eukaryotic initiation factor 2 (eIF2α) which limits translation of cellular and viral proteins [14]. Replication of retro- and some DNA viruses can be blocked by sterile alpha motif and HD-domain containing protein 1 (SAMHD1), which decreases the cell dNTP pool. The last step in the viral life cycle is escape from the cell. The ISG Tetherin traps virions of many enveloped viruses by anchoring them to the host cell.
Systemic autoimmunity: Beside its importance in the control of pathogens, IFN-I plays various roles during autoimmune diseases. In systemic lupus erythematosus (SLE) elevated levels of IFN-I are well recognized and are thought to contribute to pathogenesis [15]. Since long a role of interferon was described in type I diabetes [16]. In animal models onset of diabetes could be inhibited by blocking interferon gamma [17]. Also type I interferon can accelerate onset of type I diabetes [18-20]. Such hyperactivation of the immune response can be induced by strong activation of pattern recognition receptors [21]. In fact, a mutation in IFIH1 (Interferon Induced With Helicase C Domain 1) coding for MDA5, a sensor of viral nucleic acids and important inducer of type I interferon, is associated with increased onset of type I diabetes [22, 23] or SLE [24].
Interferons in central nervous system (CNS) homeostasis: First evidence for constitutively expressed type I IFN in the healthy brain was provided by Goldmann et al. [25] in a mouse model, showing that Usp18 deficient microglia failed to downregulate IFN induced genes, resulting in a hyperactive IFN-I state. Low level IFN-β production enhances activation of microglia and phagocytosis of myelin debris and apoptotic cells in the CNS, thereby diminishing inflammation. Endogenous production of IFN-β by microglia was also shown in a myelin oligodendrocyte glycoprotein - experimental autoimmune encephalomyelitis (MOG-EAE) model were microglia was apparent in inflamed lesions associated with myelin debris [26]. On the other hand, complete absence of IFN-β was accompanied with neurodegeneration [27]. These data implicate that fine-tuning of IFN signaling is important not only during infection but also for brain homeostasis.
Interferon induction and viruses in the brain
Microglia are resident macrophages in the CNS and play an important role in physiological and immunological processes in the brain. Furthermore, they are the main producers of IFN-I in the CNS following HSV-1 infection [28]. Astrocytes respond to a variety of neurotropic viruses; i.e. Rabies virus, vesicular stomatitis virus and Theiler's murine encephalomyelitis virus, with IFN-β production [29]. In fact, astrocytes were shown to express TLR3, which leads to production of IFN-I via phosphorylation of IRF3 [30]. In line, infection of the brain with a Rabies virus leads to fast induction of IFN-I [31]. In an animal model of simian and human immunodeficiency viruses (SIV and HIV respectively) infection, IFN-α production can be detected in the brain [32]. In a mouse model of La Crosse virus (LACV) infection, where IFN-b producing cells could be visualized, it was seen that both, microglia and astrocytes were able to produce IFN-b [33]. Studies on human cerebral organoids (COs), containing a variety of developing neurons revealed that LACV is capable of infecting neurons, which increases apoptosis in the cell cultures [34]. Responses in cells varied, depending on developmental stage, revealing that committed neurons, expressing lower levels of IFN-stimulated genes (ISGs) underwent apoptosis at a higher rate. Therefore, neuronal maturation increases the susceptibility of neurons to LACV-induced apoptosis, due to lower responsiveness to virus-induced IFN [34].
Upon brain infection of the lentiviruses, human and feline immunodeficiency viruses (HIV-1 and FIV, respectively), neuronal injury, inflammation, and neurobehavioral abnormalities can occur [35]. In a separate study, it was shown that interferon-induced genes act on the human brain microvascular endothelial cells. This might at least partially explain blood-brain barrier dysfunctions during HIV infection [36]. Transcriptomic network analyses showed a preponderance of genes involved in IFN-I signaling, which was verified by increased expression of the IFN-I-associated genes, Mx1 and CD317, in brains from HIV-infected patients [35]. In vivo studies of animals infected with the FIV strains, FIV(ch) or FIV(ncsu), revealed that FIV(ch)-infected animals displayed deficits in memory and motor speed compared with the FIV(ncsu)- and mock-infected groups [35].
Also reovirus infection can induce IFN-I in the brain [37]. Following intracranial (i.c.) inoculation with either serotype 3 (T3) or serotype 1 (T1) reovirus, increased expression of IFN-α, IFN-β, and myxovirus-resistance protein 1 (Mx1; a prototypical IFN-stimulated gene) in mouse brain tissue [37]. Lack of this IFN-I response accelerated lethality of mice, suggesting a protective role of IFN-I in the brain [37]. In line, the coronavirus mouse hepatitis virus (MHV) induced IFN-b in the brain, which was important for control of the infection [38]. MDA5 sensing of ssRNA was required for recognition of MHV and induction of IFN-I in microglia [38].
Interferon accumulation in the developing brain
Dependent on the stage of pregnancy certain infections, known as TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus) and other viral infections, like parvovirus B19, Varicella and Zika virus severely affect the fetus. Beside a number of other symptoms, CNS abnormalities like microcephaly, hydrocephalus, and cerebral calcification are common.
Zika virus has recently received attention, as it causes severe fetal pathology and debilitating impairments to human infants, including fetal death, brain lesions, in utero growth restriction, and microcephaly [39, 40]. A recent study used porcine animal models and found in animals with no birth defects high IFN-α blood plasma levels one month after birth, while affected offspring showed dramatic IFN-α shutdown during social stress [41]. They therefore concluded that fetal Zika virus infection altered type I IFN response and molecular brain pathology, which persists after birth in offspring in the absence of congenital Zika syndrome [41].
Neural crest cell (NCC) migration is mandatory for normal cerebral cortex development and mutations in the DCX (double cortex X-linked) gene, results in abnormal neuronal migration resulting in microcephaly and developmental delay [42]. Recently Pallocca et al. [43] have shown in a migration inhibition of neural crest (MINC) assay, that prolonged exposure to IFN-β affects migration of NCC at low pM concentrations. Thus, congenital exposure to IFN-β during a vulnerable stage of development contributes to a variety of CNS abnormalities as described in TORCH infection. A genetic disease described as Pseudo-TORCH 2 (PTORCH2) underscores this assumption. PTORCH2 is characterized by homozygous truncating mutations in the USP18 gene in one family [44] or compound heterozygous mutations observed in another family [45] leading to complete absence of the USP18 protein and impaired regulation of IFN-I expression. Patients presented with a variety of neurological symptoms including microcephaly, calcification, thrombocytopenia and others. Similarly, USP18 deficient mice show neuropathological symptoms and hydrocephalus [46]. Aicardi-Goutières syndrome (AGS 1-7) is a group of inflammatory diseases with a variety of severe neurological symptoms, elevated IFN-α activity in the cerebrospinal fluid (CSF) and blood and increased IFN-stimulated gene (ISG) signatures in peripheral blood, in the absence of infection [47]. Therefore, these diseases are also known as interferonopathies. Mutations in genes encoding proteins involved in nucleotide sensing or nucleotide metabolism are related to one of the seven AGS phenotypes: TREX1 (AGS1), RNASEH2A (AGS2), RNASEH2B (AGS3), RNASEH2C (AGS4), SAMHD1 (AGS5), ADAR1 (AGS6) and IFIH1 (AGS7). Impaired nucleotide metabolism which may interfere with self- and non-self-nucleic acid discrimination together with enhanced proinflammatory IFN-I and ISGs may explain why certain autoimmune diseases occur in patients with AGS, as for instance systemic lupus erythematosus (SLE) in AGS1, AGS6 and AGS7 or Diabetes type 1 (T1D) in AGS1 and AGS3. Additionally, certain mutations in IFIH1 predispose to SLE or T1D [48].
Interferons in modulating inflammation in the brain
Recent findings have revealed distinct roles for IFN-I and IFN-γ in the recruitment of immune cells to the CNS and highlighted the importance of this process for brain maintenance and protection and/or repair [49]. Interferon therapy is one treatment option for multiple sclerosis. The benefits of IFN-b therapy were demonstrated in several studies. In a three-year, open-label study, IFN-b-1a significantly slowed the progression of whole-brain and gray matter atrophy, and of T1-hypointense LV accumulation, when compared with the control group [50]. While the precise molecular mechanism of IFN-I therapy in MS patients remains to be shown, several studies suggest, that it might be related to modification of the blood-brain barrier [51]. IFN-b therapy was further shown to act via JAK-STAT pathway [52], and phosphorylation was proposed as a marker of disease activity since it is upregulated in peripheral blood mononuclear cells (PBMC) during active phases of the disease [53]. Additionally, IFN-ß therapy non-responders showed a greater activation in the JAK-STAT signaling pathway with elevated IFNAR1 and pSTAT1 levels in monocytes [53].
In another autoimmune disease, namely systemic lupus erythematosus (SLE), IFN-I is believed to be a hallmark of disease and high levels of IFNs as well as IFN-stimulated genes (ISGs) persist chronically in patients [54]. Upregulation of ISGs is often due to IFN-γ, which is upregulated in some SLE patient groups [55, 56]. However, the IFN signature in SLE patients is quite complex and IFN-α is the most abundant in SLE patients [54], while also the IFN-Is IFN-β and IFN-ω are elevated in SLE patients blood [57]. Interestingly, it was suggested that neurotoxic lymphocytes are activated by IFN-α and thereby could mediate CNS damage in an IFN-I dependent manner [54, 58].
Role of interferon on blood-brain barrier and circulation
The blood-brain barrier protects the CNS from pathogens [59]. It is the gatekeeper for molecules and cells passaging and consists of the highly specialized brain microvascular endothelial cells, which are connected via tight and adherens junctions, associated with pericytes and surrounded by endfeet of astrocytes [60]. Changes in the blood-brain barrier are hallmarks of several diseases, including the pathogenesis of multiple sclerosis (MS). Beside the immunomodulatory function of IFN-β there is increasing evidence that IFN-β directly effects the blood-brain barrier in several species including humans [51]. Also IFN-III can protect the brain from infection. A recent study using West Nile virus infection showed, while IFN-III did not act directly antiviral, it decreased the blood-brain barrier permeability. Therefore, IFN-III protected the brain from viral spread and improved survival of mice [61]. On the other hand, the type II IFN, IFN-γ is secreted by Natural Killer (NK) and activated T cells and is a major signal for the recruitment and activation of leukocytes to sites of infection. It therefore enhances leukocyte trafficking, in a CXCL10 mediated manner, and thereby indirectly disrupts the blood-brain barrier as occurs in Rabies virus infection [62]. However, also direct effects of IFN-γ on vascular endothelia dysregulating barrier functions have been reported in vitro [63]. Disruption of the blood-brain barrier seems to facilitate entrance for circulating pathogens into the CNS, however, it can be required for cellular immunity and complete pathogen clearance from the CNS [64].
Interestingly IFN-I were shown to modulate the choroid plexus during aging [65]. By using multiorgan genome-wide analysis of aged mice, Baruch et al. found that the choroid plexus shows an IFN-I-dependent gene expression profile that was also found in aged human brains. Blocking IFN-I signaling within the aged brain partially restored cognitive function and hippocampal neurogenesis and reestablished IFN-II-dependent choroid plexus activity [65]. In line, preconditioning with poly(I:C) protects against cerebral ischemic damage [66]. Poly(I:C) treatment, which induced IFN-β in astrocytes and microglia, maintained the paracellular and transcellular transport across the endothelium and attenuated the drop in transendothelial electric resistance [66]. In line with this study, TLR-activation led to induction of interferon regulatory factor (IRF)-mediated transcription in the brain, which correlated with ischemic resistance. Using mice deficient in IRF3 or IRF7 the authors could prove the importance of IFN induced genes in this process [67].
Role of IFN-I in cognitive and psychological functions and degeneration
Sickness behavior and cognitive dysfunction occur frequently in virus-infected individuals. In a recent study, Blank et al. found that behavioral alterations were specifically dependent on brain endothelial and epithelial IFN-α receptor chain 1 (IFNAR1) [68]. Mechanistically the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity [68]. In line with these findings IFN-I treatment can induced depression as a side effect. This is seen in patients, which are treated with IFN-I as hepatitis C virus (HCV) therapy. In a recent study 15 genes that are associated with the development of severe depression, were upregulated during the standard therapy of HCV with IFN-α and ribavirin [69]. The onset of depression correlated with serum levels of brain-derived neurotrophic factor [70]. These findings suggest that the effect of IFN-α-induced immune activation on depression may be explained in part by alterations in neuroprotective capacity [70]. In line with these data additional studies suggest that the degeneration of axons containing serotonin and noradrenaline is involved in the pathophysiology of depression [71]. An immune histochemical study showed that IFN-α induced decreases in the density of serotonergic axons in the ventral medial prefrontal cortex and amygdala and decreases in the density of noradrenergic axons in the dorsal medial prefrontal cortex, ventral medial prefrontal cortex, and dentate gyrus [71]. Also cognitive functions of the brain can be modulated by IFN-I. A mouse study, where HIV is inoculated into the brain of mice, shows that HIV induces IFN-α in brains of these mice, which correlated with working memory errors for mice with HIV infected macrophages [72].
Pro inflammatory cytokines like Interleukin-1 β (IL1) and tumor necrosis factor α (TNF-α) have been found to be important regulators of sleep [73, 74]. Chronic insomnia was further shown to be related to increased IL-6 levels as well as a shift from nighttime to daytime IL-6 and TNF-α secretion [75]. Furthermore, IFN-α treated HCV patients show reduced sleep continuity and depth and induced a sleep pattern consistent with insomnia [76]. Therefore, sleep disturbances can relate to altered levels of inflammatory mediators.
Conclusion
Under physiological conditions, CNS astrocytes produce IFN-β, which is of high relevance for homeostasis in the brain, by regulating phagocytic removal of myelin debris by microglia and integrity of the blood-brain barrier. Neurotropic viruses, including La Crosse virus (LACV), infect the brain and are battled against by innate immune responses of microglia and astrocytes, the production of IFN-α and/or –β, and followed by an adaptive immune response. Disruption of the blood-brain barrier seems to facilitate entrance of peripheral lymphocytes and is therefore often required for complete pathogen clearance from the CNS. However, inflammation in the brain can also cause neurological impairment and whenever neurological defects remain is dependent on the infecting virus itself as well as viral loads and presumably constitution, and lastly the genetic background of the host. Viral infections during vulnerable phases of embryonic development cause severe fetal pathology and debilitating impairments to human infants. The roles of IFN in these scenarios are diverse and include deficits due to overproduction of IFN during the developmental stage of the brain as seems to be the case in pseudo-TORCH2. Genetic mutations causing a chronic production of IFN-α in the cerebrospinal fluid cause sever neurological symptoms as in Aicardi-Goutières syndrome (AGS) and are characterized by a IFN-stimulated genes (ISGs) signature in the peripheral blood. Lastly, altered levels of IFNs are involved in autoimmune diseases as in systemic lupus erythematosus and furthermore can cause psychological and cognitive impairments.
Dissection of the various effects of IFN-I in the brain is still demanding. A broad range of phenotypes in interferon mediated or accompanied diseases is well and long term documented in humans compared to the experimental conditions in the inbred mice. However, in mice compared to the human, the immunological conditions directly in the brain can be approached experimentally, hopefully revealing mechanistic insights into associated pathologies.
Disclosure Statement
The authors declare no competing interests.
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