Mechanisms of pathogenic microglial populations in CNS inflammation - PROJECT SUMMARY/ABSTRACT In multiple sclerosis (MS), microglia contribute to oxidative stress and tissue damage leading to the progression of disease. The molecular mechanisms that regulate the activation of microglia towards oxidative stress phenotype remain poorly understood, hindering the development of effective treatments. Blood-brain barrier (BBB) damage is an early and common pathology linked to microglial activation, oxidative stress, and neurodegeneration in MS. Our prior studies have identified that microglia sense BBB leaks and blood proteins through the transcriptional activation of oxidative stress, metabolic and interferon signaling pathways in neurodegenerative disease models. We identified the blood coagulation protein fibrin to be both necessary and sufficient for the induction of pathogenic microglia. Our preliminary observations profiling the transcriptional and epigenetic landscape of pro-oxidant microglia in the experimental autoimmune encephalomyelitis (EAE) model of MS has identified the ACOD1-Itaconate axis a potential molecular switch governing pathogenic microglia at sites of BBB damage and fibrin deposits. Aconitate decarboxylase 1 (Acod1) catalyzes the production of itaconate, an anti-inflammatory metabolite. Our data suggests that Acod1 is epigenetically repressed in chronically activated pro-oxidant microglia and that therapeutic administration of itaconate ameliorates relapsing EAE severity and oxidative stress. Prior research and our results have led us to hypothesize that Acod1-itaconate axis controls neuroprotective microglia responses in CNS inflammation. This proposal will test how ACOD1- itaconate regulates the transcriptional activation of pro-oxidant microglia in EAE (Aim 1), whether fibrin-CD11b signaling deregulates ACOD1-itaconate axis in human induced pluripotent stem cell derived microglia and in the EAE model (Aim 2); and whether interferon signaling drives pro-oxidant microglia activation via epigenetic remodeling in CNS inflammation (Aim 3). In summary, this project studies pro-oxidant microglial populations and the molecular and cellular mechanisms that control it, with the goal to identify novel immunomodulatory therapeutic targets for MS.
