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IFN secreted by microglia mediates clearance of myelin debris in CNS autoimmunity

Kocur, M;Schneider, R;Pulm, AK;Bauer, J;Kropp, S;Gliem, M;Ingwersen, J;Goebels, N;Alferink, J;Prozorovski, T;Aktas, O;Scheu, S;

Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS) leading to progressive neurological disability. Interferon (IFN) represents a standard treatment for relapsing-remitting MS and exogenous administration of IFN exhibits protective effects in experimentally induced CNS autoimmunity. Also, genetic deletion of IFN in mice leads to an aggravation of disease symptoms in the MS model of experimental autoimmune encephalomyelitis (EAE). However, neither the underlying mechanisms mediating the beneficial effects nor the cellular source of IFN have been fully elucidated.,In this report, a subpopulation of activated microglia was identified as the major producers of IFN in the CNS at the peak of EAE using an IFN-fluorescence reporter mouse model. These IFN expressing microglia specifically localized to active CNS lesions and were associated with myelin debris in demyelinated cerebellar organotypic slice cultures (OSCs). In response to IFN microglia showed an enhanced capacity to phagocytose myelin in vitro and up-regulated the expression of phagocytosis-associated genes. IFN treatment was further sufficient to stimulate association of microglia with myelin debris in OSCs. Moreover, IFN-producing microglia mediated an enhanced removal of myelin debris when co-transplanted onto demyelinated OSCs as compared to IFN non-producing microglia.,These data identify activated microglia as the major producers of protective IFN at the peak of EAE and as orchestrators of IFN-induced clearance of myelin debris.