No abstract

17In early autoimmune neuroinflammation, interferon (IFN)g and its upregulation of the 18 immunoproteasome (iP) is pathologic. However, during chronic multiple sclerosis (MS), IFNg has 19 protective properties and, the role of the iP remains to be fully elucidated. Here, we demonstrated 20 that IFNg signaling in regional astrocytes induces the iP and protects the CNS during 21 autoimmunity. In MS tissue, iP expression was enhanced in spinal cord compared to brainstem 22 lesions, which correlated with a decrease in oxidative stress. In vitro, IFNg stimulation enhanced 23 iP expression, reduced reactive oxygen species burden, and decreased oxidatively damaged and 24 poly-ubiquitinated protein accumulation preferentially in human spinal cord astrocytes, which was 25 abrogated with the use of the iP inhibitor, ONX 0914. During the chronic phase of an MS animal 26 model, experimental autoimmune encephalomyelitis (EAE), ONX 0914 treatment exacerbated 27 disease and led to increased oxidative stress and poly-ubiquitinated protein build-up. Finally, mice 28 with astrocyte-specific loss of the IFNg receptor exhibited worsened chronic EAE associated with 29 reduced iP expression, enhanced lesion size and oxidative stress and poly-ubiquitinated protein 30 accumulation in astrocytes. Taken together, our data reveal a protective role for IFNg in chronic 31 neuroinflammation and identify a novel function of the iP in astrocytes during CNS autoimmunity. 32 33 34 Multiple sclerosis (MS) is the most common chronic inflammatory and 35 neurodegenerative disease of the central nervous system (CNS) (1). During the 36 pathogenesis of MS, there is immune cell infiltration, demyelination, and reactive gliosis 37within CNS lesions in multiple regions (2). Relapsing-remitting MS (RRMS) is a subtype 38 that affects approximately 85% of patients and is characterized by episodic periods of 39 neurological dysfunction, often associated with inflammation, followed by partial or 40 complete recovery. A significant proportion of these patients go on to develop secondary 41 progressive MS (SPMS), during which they have fewer remissions and increasing 42 atrophy, correlating with progressive disability (3, 4). Primary progressive (PPMS) a third 43 subtype of MS, affects approximately 15% of patients and is associated with continuous, 44 progressive loss of neurological function after initial diagnosis, without periods of 45 remission (5, 6). Of note, it is thought that the pathology associated with RRMS has a 46 relatively significant inflammatory component, while in SPMS and PPMS, inflammation is 47 an animal model of MS, astrocytes are known to exhibit regional heterogeneity in gene 58 expression and response to inflammation (17)(18)(19). Indeed, ablation of astrocytes following 59 several types of CNS injury leads to sustained inflammation, impaired repair, and 60 increased neurodegeneration (20-29), suggesting that a diverse astrocytic response is 61 critical in healthy tissue preservation and support, minimizing CNS bystander damage 62 during...