IFN-γ regulates transcription of key molecules to prevent progressive experimental autoimmune encephalomyelitis

Abstract

Abstract Multiple sclerosis (MS) is the most common disabling neurological condition of young adults. Most patients are initially diagnosed with relapsing-remitting MS. Problematically; 10 years after diagnosis approximately 60% of MS patients will have converted from the relapsing-remitting form of MS to secondary-progressive MS despite treatments. 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), and is often suppressed during treatments for MS. However, 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 fully elucidated. We hypothesize that IFN-g prevents disease progression in this progressive EAE model by regulating the expression of molecules that promote the resolution of lipid peroxidation and clearance of myelin debris in the CNS during EAE. We identified a number of key molecules associated with lipid peroxidation which are temporally dysregulated in the absence of IFN-gR using qRT-PCR. To discover additional molecules involved in disease progression we have performed comprehensive RNA sequencing on the CNS of IFN-gR−/− vs WT mice through the course of disease. We will present the result of the analysis of these molecules and supporting studies. The results of our studies will contribute to a more thorough understanding of the underlying mechanisms and may lead to new treatments to prevent progression of MS.