Reduction in CD11c+ microglia promotes secondary progression in autoimmune demyelination

Secondary progressive multiple sclerosis (SPMS) is a common outcome of relapsing-remitting form of multiple sclerosis (MS). The cellular and molecular mechanisms of SPMS remain unclear and there is an unmet need for treatments to prevent or stop secondary progression (SP). Here we demonstrate that reduction in CD11c+ microglia promotes disperse coalescent immune cell infiltration of the spinal cord white matter causing clinical deterioration and SP in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Knockout of p38a in CD11c+ cells in female mice resulted in reduction in CD11c+ microglia number and high incidence of SP EAE associated with immune cell parenchymal infiltration. In contrast, increased numbers of CD11c+ microglia in males resulted in detention of immune cells in perivascular areas and prevented SP. We conclude that CD11c+ microglia are essential to halt immune cells from re-entering CNS parenchyma in SP EAE. Our data uncovered a sex-biased mechanism of p38α signaling in CD11c+ microglia and revealed a novel regulatory function of CD11c+ microglia in chronic autoimmune neuroinflammation.