Regional astrocyte interferon-γ signaling regulates immunoproteasome-mediated protection during chronic autoimmunity

In early autoimmune neuroinflammation, interferon (IFN){gamma} and its upregulation of the immunoproteasome (iP) is pathologic. However, during chronic multiple sclerosis (MS), IFN{gamma} has protective properties and, the role of the iP remains to be fully elucidated. Here, we demonstrated that IFN{gamma} signaling in regional astrocytes induces the iP and protects the CNS during autoimmunity. In MS tissue, iP expression was enhanced in spinal cord compared to brainstem lesions, which correlated with a decrease in oxidative stress. In vitro, IFN{gamma} stimulation enhanced iP expression, reduced reactive oxygen species burden, and decreased oxidatively damaged and poly-ubiquitinated protein accumulation preferentially in human spinal cord astrocytes, which was abrogated with the use of the iP inhibitor, ONX 0914. During the chronic phase of an MS animal model, experimental autoimmune encephalomyelitis (EAE), ONX 0914 treatment exacerbated disease and led to increased oxidative stress and poly-ubiquitinated protein build-up. Finally, mice with astrocyte-specific loss of the IFN{gamma} receptor exhibited worsened chronic EAE associated with reduced iP expression, enhanced lesion size and oxidative stress and poly-ubiquitinated protein accumulation in astrocytes. Taken together, our data reveal a protective role for IFN{gamma} in chronic neuroinflammation and identify a novel function of the iP in astrocytes during CNS autoimmunity.