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• Astrocytes play both protective and detrimental roles in MS and EAE. • The functions of astrocytes in MS and EAE are decided by the stimuli provided by the local milieu. • Astrocytes may become a potential therapeutic target for the treatment of MS. Neuropathology in the human autoimmune disease multiple sclerosis (MS) is considered to be mediated by autoreactive leukocytes, such as T cells, B cells, and macrophages. However, the inflammation and tissue damage in MS and its animal model experimental autoimmune encephalomyelitis (EAE) is also critically regulated by astrocytes, the most abundant cell population in the central nervous system (CNS). Under physiological conditions, astrocytes are integral to the development and function of the CNS, whereas in CNS autoimmunity, astrocytes influence the pathogenesis, progression, and recovery of the diseases. In this review, we summarize recent advances in astrocytic functions in the context of MS and EAE, which are categorized into two opposite aspects, one being detrimental and the other beneficial. Inhibition of the detrimental functions and/or enhancement of the beneficial functions of astrocytes might be favorable for the treatment of MS. [ABSTRACT FROM AUTHOR]

Astrocytes are critical regulators of neuroinflammation in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Growing evidence indicates that ubiquitination of signaling molecules is an important cell‐intrinsic mechanism governing astrocyte function during MS and EAE. Here, we identified an upregulation of the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) in astrocytes during MS and EAE. Mice with astrocyte‐specific OTUB1 ablation developed more severe EAE due to increased leukocyte accumulation, proinflammatory gene transcription, and demyelination in the spinal cord as compared to control mice. OTUB1‐deficient astrocytes were hyperactivated in response to IFN‐γ, a fingerprint cytokine of encephalitogenic T cells, and produced more proinflammatory cytokines and chemokines than control astrocytes. Mechanistically, OTUB1 inhibited IFN‐γ‐induced Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling by K48 deubiquitination and stabilization of the JAK2 inhibitor suppressor of cytokine signaling 1 (SOCS1). Thus, astrocyte‐specific OTUB1 is a critical inhibitor of neuroinflammation in CNS autoimmunity. Synopsis: The deubiquitinating enzyme OTUB1 regulates cell signaling by blocking ubiquitin transfer from E2 conjugating enzymes to E3 ligases or by cleavage of ubiquitin chains from target proteins, but the in vivo cell type‐specific function of OTUB1 is largely unknown. During CNS autoimmunity, human and murine astrocytes upregulate OTUB1, which limits CNS pathology by inhibiting IFN‐γ‐induced activation of the JAK2/STAT1 pathway and concomitant chemokine and cytokine production in astrocytes. OTUB1 expression of astrocytes is induced in the CNS of treatment‐naïve patients with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis.OTUB1 inhibits IFN‐γ‐induced JAK2/STAT1 signaling by K48 deubiquitination and stabilization of the JAK2 inhibitor SOCS1.OTUB1‐dependent inhibition of the JAK2/STAT1 signaling limits IFN‐γ‐induced cytokine and chemokine production of astrocytes.OTUB1 expression in astrocytes ameliorates the clinical severity of murine experimental autoimmune encephalomyelitis by limiting astrocytic cytokine and chemokine production, recruitment of encephalitogenic T cells to the CNS, and demyelination. [ABSTRACT FROM AUTHOR]