Oxysterols promote encephalitogenic CD4 + T cell migration during neuroinflammation

Abstract

Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS) leading to progressive neurological dysfunction. Interferon beta (IFNbeta) represents a standard treatment for relapsing–remittingMS that decreases the frequency of relapses and slows disease progression. Exogenous administration of IFNbeta was also demonstrated to exert protective effects in theMS animalmodel of experimental autoimmune encephalomyelitis (EAE) while genetic deletion of IFNbeta in mice leads to an aggravation of disease symptoms. This suggests IFNbeta producing cells as a target for new therapy strategies for autoimmune CNS inflammation. However, neither the source of IFNbeta nor its immunomodulatory mechanisms are known. In this report activated residentmicroglia were identified as themajor IFNbeta source in the CNS during peak EAE presentation using a YFP knock-in reportermodel for IFNbeta. IFNbeta-producingmicroglia migrated efficiently towardsmyelin debris in organotypic slice cultures and IFNbeta deficient microglia failed to induce efficient removal of myelin degradation products in this ex vivo model of lysolecithininduced demyelination, underscoring the prominent role for IFNbeta in controlling myelin clearance. Treatment with IFNbeta alone was sufficient to stimulate specific phagocytotic uptake of degraded myelin by cultured microglia indicating that IFNbeta regulates myelin phagocytosis in primary microglia. These data identify activated microglia as the major endogenous producers of protective IFNbeta at the peak of EAE and demonstrate their involvement in the clearance of myelin debris and possibly neuronal regeneration in CNS autoimmunity. doi:10.1016/j.jneuroim.2014.08.454