Alternatively activated brain-resident macrophages rapidly acquire inflammatory properties following CNS infection (INC6P.301)

Abstract

Abstract Classic (M1) and alternative (M2) polarization of macrophages has been broadly studied in vitro but its relevance in the context of meningeal inflammation is unknown. The meningeal and perivascular spaces of the central nervous system (CNS) are inhabited by specialized macrophages. To gain novel insights into these cells, we analyzed the naive and virally infected brain using intravital two-photon microscopy (TPM) and flow cytometry. Examination of the naive brain by TPM revealed that meningeal and perivascular macrophages are highly dynamic and constantly survey their immediate surroundings similar to microglia. Under steady state conditions, we uncovered that they are maintained in a M2 state, which likely facilitates brain homeostasis. Interestingly, during the development of fatal viral meningitis induced by lymphocytic choriomeningitis virus, these cells were directly engaged by infiltrating virus-specific CD8+ T cells following acquisition of viral antigen and conversion into an inflammatory M1 phenotype. Mechanistically, the M2 to M1 transition occurred in the absence of CD8+ T cells and relied instead on innate cytokine release. These data indicate that meningeal and perivascular macrophages are highly plastic cells that can rapidly convert from a M2 to M1 phenotype and participate in the antiviral defense against an invading pathogen. This rapid inflammatory transition may explain why most CNS immune responses first develop in the meningeal and perivascular spaces.