Mechanisms by which IFN-γ mitigates lipid peroxidation that leads to progressive experimental autoimmune encephalomyelitis

Abstract

Abstract Multiple sclerosis (MS) is the most common demyelinating autoimmune disease of the central nervous system affecting over 2.3 million people worldwide. Although most patients are initially diagnosed with relapsing-remitting MS, the vast majority of these will eventually develop progressive MS. Importantly, the mechanisms that contribute to the progression of MS are largely unknown. IFN-γ, a well-studied pro-inflammatory cytokine, has long been implicated in the pathogenesis of MS and its preclinical model, experimental autoimmune encephalomyelitis (EAE). Although pro-inflammatory, disease-promoting effects are well documented for IFN-γ, paradoxically, protective functions have also been demonstrated for this cytokine. We are interested in protective mechanisms of IFN-γ. Previous studies in our lab revealed that mice lacking IFN-γ signaling developed severe and progressive EAE due to increased presence of myelin debris and lipid peroxidation in the CNS, the cause of which is yet to be elucidated. We hypothesize that IFN-γ helps regulate expression of scavenger receptors, antioxidant molecules, and pro-oxidant molecules in order to promote resolution of lipid peroxidation and clearance of myelin debris in the CNS during EAE. We are currently investigating key scavenger receptor, antioxidant, and pro-oxidant molecule expression in IFN-γR−/− vs. wild type mice during EAE. Our results will contribute to a better understanding of the underlying mechanisms and may lead to new treatments to prevent progression of MS.