Dynamic role of monocytes and meningeal macrophages in bacterial meningoencephalitis

1.

Macrophages in the dura mater are substantial contributors to the immune defense of the brain, however, their site-specific origin and function in bacterial infections of the central nervous system are incompletely understood.

In a natural model of streptococcal meningoencephalitis, where bacteria systemically spread via the bloodstream to the brain, we found streptococci to be largely restricted in the meninges. Further sporadic spread of bacteria to the underlying brain parenchyma caused a region-restricted microglia activation. Invasion of monocytes, but not granulocytes into brain and leptomeninges correlated to the disease severity. Inflammation in the dura was accompanied by activation and loss of dural macrophages, and by the rapid engraftment of highly activated monocytes. In addition, monocyte progenitors in the skull marrow underwent drastic changes and acquired a more immature phenotype likely due to infection-induced emergency myelopoiesis. Notably, while dural monocytes were derived from adjacent skull marrow in a CCR2-independent fashion, the high demand for dural monocytes in streptococcal meningoencephalitis required intact CCR2 signalling and involved the long bone marrow, indicating heterogeneity in monocyte recruitment. Furthermore, meningoencephalitis increased monocyte progeny from monocyte-dendritic cell progenitors compared to the homeostatic, granulocyte-monocyte progenitor-dominated origin. Accordingly, monocytes in the dura, recruited from distinct reservoirs depending on disease-inherent needs, are intertwined with the disease course and may thus offer opportunities for therapeutic interventions.