Type I interferons as ambiguous modulators of chronic inflammation in the central nervous system - PubMed (original) (raw)
Type I interferons as ambiguous modulators of chronic inflammation in the central nervous system
Marco Prinz et al. Front Immunol. 2012.
Abstract
Type I interferons (IFNs) were originally identified as antiviral effector molecules that exert pleiotropic physiological processes ranging from immune modulation, control of proliferation, apoptosis to antitumor activity. However, type I IFNs were recently also shown to apply both beneficial and detrimental effects to the central nervous system (CNS) and a tightly balanced equilibrium between cellular activation and inhibition seems to be essential to maintain homeostasis within the CNS. In inflammatory pathologies affecting the CNS, type I IFNs are in the center of attention not only because interferon beta (IFN-β) is used as a standard therapeutic in the treatment of relapsing-remitting multiple sclerosis (MS), but also as type I IFN expression is associated with distinct pathologies. Despite the great efficiency of IFN-β in reducing MS relapses and attenuation of novel inflammatory lesions is well documented, underlying molecular mechanisms and cellular target specificities are just beginning to emerge. In contrast to the curative effects, aberrant activation of the type I IFN response were also recently shown to be associated with detrimental effects exemplified by the Aicardi-Goutières syndrome (AGS), a severe disabling autoimmune inflammatory encephalopathy. This review will highlight the dual role of type I interferons during chronic CNS inflammation. Recently uncovered molecular and cellular mechanisms in the etiology of AGS and experimental autoimmune encephalomyelitis (EAE), the murine model of MS will be highlighted.
Keywords: AGS; MDA5; RIG-I; RNASEH2; SAMHD1; TREX1; experimental autoimmune encephalomyelitis; interferon.
Figures
Figure 1
Overview of typical signaling cascades inducing type I Interferon expression. Upon ligand engagement, several toll-like receptors (TLRs) and RIG-I like helicases (RLHs) induce transcription of type I interferons (IFN). TLR4 located at the cell surface is typically induced extracellular while TLR3, TLR 7/8, and TLR9 sense pathogen-derived single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), and unmethylated DNA (CpG DNA) within the cell sequestered from the cytoplasmic compartment. Intracellular TLRs are localized, traffic, and initiate signaling cascades in membrane surrounded compartments like the endoplasmic reticulum, endosomes, lysosomes, and phagocytic vesicles. Upon ligand binding, TLR4 is endocytosed (indicated by dashed arrows). Downstream signaling inducing type I IFN is mediated by initial binding to either MyD88 (TLR7/8/9) or TRIF (TLR3/4), followed by recruitment of multicomponent protein complexes. Typically a complex with TLR3 or TLR4 together with TRIF and TRAF3 activates the kinase TBK1 mediating phosphorylation of IRF3, which subsequently forms homodimers, translocates to the nucleus, and initiates type I IFN gene expression. MyD88 recruited to TLR7/8/9 complexes with IRAK1, TRAF6, TRAF3, and the kinases TAK1 and IKKα, which phosphorylate and thus activate IRF7 to drive type I IFN expression. The cytoplasmic RLHs MDA5 and RIG-I recognize longer RNAs like poly I:C or 5′-3-P-RNA respectively and engage IPS at the mitochondrial membrane. Recruitment of a complex containing TBK1 induces phosphorylation and thus dimerization of IRF3 followed by type I IFN gene expression. Independent from TLR and RLH intracellular, non-CpG DNA, and cyclic-di-GMP are sensed in a STING dependent manner. STING interacts with RIG-I and activates type I IFN transcription via the IRF3 axis but is also capable to recruit STAT6 to the ER followed by TBK1 mediated STAT6 phosphorylation.
Figure 2
Model for the role of cytoplasmic nucleic acid homeostasis in the etiology of Aicardi–Goutieres syndrome (AGS). TREX1 is an 5′–3′ Exonuclease which degrades cytoplasmic single-stranded DNA (ssDNA) originating from reverse transcription of endogenous retrotransposons. Lack of TREX1 activity results in the congestion of ssDNA thereby augmenting the pool of nucleic acids in the cytoplasm. SAMHD1 cleaves inorganic triphosphate from deoxynucleotides and thus restricts the cytoplasmic dNTP concentrations hence constraining reverse transcription by limiting the amount of “building blocks” for DNA synthesis. SAMHD1 mutations would eliminate this dNTP control mechanism, enhance the dNTP pool, and could thus fuel reverse transcription from endogenous retroelements resulting in increased levels of cytoplasmic ssDNA. RNASEH2 is an endonuclease composed of three subunits and required to cleave ribonucleotides from RNA:DNA duplexes which arise from intracellular processes. Lack of function mutations in RNASeH2 would thus also impair the control of nucleic acid homeostasis. Thus mutations in any kind of the genes mentioned above which were found in AGS patients would lead to the accumulation of nucleic acids in the cytoplasm. These aberrant levels are sensed by cytoplasmic DNA sensors originally designated to detect viral infections. Consequently the initiated signaling cascade activates interferon regulatory transcription factors (IRFs) for type I IFN induction and drive autoimmune disease onset.
Figure 3
Model for negative regulation of sterile CNS inflammation by RIG-I like helicases (RLHs). In dendritic cells activation of RLHs RIG-I or MDA5 by 5′triphosphate RNA or polyI:C complexed to liposomes (cPolyI:C) respectively, recruits IPS-1 to the RLH. This initiates a signaling cascade which involves TBK1 mediated phosphorylation of IRF3 and/or IRF7 which upon dimerization enter the nucleus and lead to the expression of type I IFN. Secreted type IFNs (IFN) can either bind to type I interferon receptor (IFNAR) in an autocrine or paracrine manner and stimulate the expression of interferon-stimulated target genes (ISGs). While lack of IPS-1 leads to exacerbated disease pathology in the EAE model of sterile inflammation, RLH stimulation improved clinical signs of disease and inhibits TH1 and TH17 expansion and survival. This regulation is type I IFN mediated as the “therapeutic effect” of RLH stimulation is abrogated in IFNAR deficient mice. However, mice specifically lacking IFNAR on monocytes, macrophages, microglia, or granulocytes like wildtype mice showed reduced symptoms upon RLH induction. IFNAR signaling on these cells is thus dispensable for the suppressive effect of RLH engagement. In contrast, when mice specifically lacking IFNAR on dendritic cells were used, RLH treatment did not ameliorate autoimmunity clearly showing that interferon stimulation in this particular celltype is essential for IFN mediated TH1 and TH17 inhibition and disease improvement.
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