Infection and natural inflammatory aging drive monocyte engraftment into the meninges that impairs CNS immunity
Rejane Rua, Jane Lee, Alexander Silva, Dragan Maric, Kory Johnson, Dorian B. McGavern Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
Tissue-resident macrophages have an embryonic origin and can be replenished by blood monocytes in some tissues during adulthood. Under steady-state conditions, infiltrating monocytes can share phenotypic and genotypic features with their embryonically-derived counterparts. However, little is known about the properties of monocytes / macrophages that may establish tissue residency after an inflammatory challenge. We used intravital imaging paired with flow cytometry and transcriptomic approaches to address this question. The meninges of the central nervous system (CNS) are populated by a dense network of specialized macrophages that serve as immune sentinels. Following infection by lymphocytic choriomeningitis virus (LCMV), these resident macrophages become activated by innate inflammatory cytokines, acquire viral antigens, and are targeted by infiltrating cytotoxic T lymphocytes (CTL), which leads to their depletion. Innate cytokines and chemokines released by CTL also promote a massive recruitment of inflammatory monocytes from the periphery. Surprisingly, these infiltrating monocytes engraft the meningeal niche and remain in situ several months after viral clearance. This leads to significant phenotypic and functional changes in meningeal immunity - a defect that can be partially restored by blocking IFNγ signaling. Macrophages that establish residency in the meninges after an inflammatory event are deficient in bacterial and immunoregulatory sensors, which impedes their ability to detect pathogens and dampen subsequent meningeal immune responses. Interestingly, similar functional defects were observed in naïve mice upon aging, suggesting that monocyte engraftment during the normal process of inflammatory aging can also impair CNS immunity. To test this theory, we reset the system by depleting meningeal macrophages, which promoted robust proliferation and repopulation of the meninges by resident macrophages. These cells were highly responsive to bacterial challenge and responded more efficiently than meningeal macrophages found in normal aged mice. Collectively, these data indicate that meningeal macrophages are replaced by blood-derived monocytes under steady state and inflammatory conditions - a process that can be reversed to benefit CNS immunity.
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