Interferon β-Mediated Protective Functions of Microglia in Central Nervous System Autoimmunity

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and axonal damage. It often affects young adults and can lead to neurological disability. Interferon β (IFNβ) preparations represent widely used treatment regimens for patients with relapsing-remitting MS (RRMS) with therapeutic efficacy in reducing disease progression and frequency of acute exacerbations. In mice, IFNβ therapy has been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS while genetic deletion of IFNβ or its receptor augments clinical severity of disease. However, the complex mechanism of action of IFNβ in CNS autoimmunity has not been fully elucidated. Here, we review our current understanding of the origin, phenotype, and function of microglia and CNS immigrating macrophages in the pathogenesis of MS and EAE. In addition, we highlight the emerging roles of microglia as IFNβ-producing cells and vice versa the impact of IFNβ on microglia in CNS autoimmunity. We finally discuss recent progress in unraveling the underlying molecular mechanisms of IFNβ-mediated effects in EAE.

Interferon-β Plays a Detrimental Role in Experimental Traumatic Brain Injury by Enhancing Neuroinflammation That Drives Chronic Neurodegeneration

“…However, studies based on IFNAR signaling cannot pinpoint the functional contribution of IFN-␣ and IFN-␤ during neuroprotection. Moreover, similar to its protective actions in MS (Scheu et al, 2019), exogenous administration of IFN-␤ following spinal cord injury improves functional recovery in mice, in part by reducing lipid peroxidation and inflammatory cytokines (Gok et al, 2007;Sandrow-Feinberg et al, 2010). This highlights the complex role of IFN-␤ during secondary injury and CNS repair.…”

Glial Factors Regulating White Matter Development and Pathologies of the Cerebellum

“…As a therapeutic agent, IFNβ represents a widely used treatment regimen for patients with relapsing-remitting MS (RRMS) [92] and shows treatment efficacy by reducing disease progression and also frequency of exacerbation. In animal experiments, induction of endogenous IFNβ by polyinosinic:polycytidylic acid [poly(I:C)] treatment diminished the severity of EAE, and genetic deletion of IFNβ or its receptor in contrast enhanced clinical score, with more extensive CNS inflammation and demyelination [93]. Treament with IFNβ also reduced axonal damage in a cerebellar slice culture assay with LPS stimulation [94].…”

Therapeutic STING activation boosts microglia phagocytosis and ameliorates depression-like behaviors during chronic restraint stress

“…Previously, Toll/interleukin-1 receptor domain-containing adapter inducing IFN-β (TRIF) de cient microglia exhibited an increased threshold for activation of interferon-regulated genes, suggesting that IFN-β may enhance phagocytic activity [37]. In experimental autoimmune encephalomyelitis, IFN-β producing microglia mediated an enhanced removal of myelin debris compared to IFN-β non-producing microglia [38]. Indeed, we observed that STING-activated microglia exhibit a superior phagocytic capacity, and IFN-β might guide positioning of microglia in the in amed central nervous system during chronic stress.…”