Microglia and border-associated macrophages play opposite roles in cerebrovascular and leukocyte responses under systemic inflammation in male mice

Microglia closely associate with the vasculature, but their roles in leukocyte trafficking and cerebral blood flow (CBF) during systemic inflammation are unclear. We show that sustained systemic inflammation leads to altered microglia-vascular interactions, leukocyte recruitment to cerebral blood vessels and reduced hypercapnia-induced vasodilation. We find that microglia and border-associated macrophages (BAMs) play distinct roles in these processes: while BAM depletion with clodronate increases leukocyte recruitment, microglia/BAM depletion with PLX5622 and the absence of microglia, but not BAMs in CSF1RΔFIRE/ΔFIRE mice, result in markedly reduced leukocyte recruitment. Supporting this, conditional microglial IL-1 deletion inhibits leukocyte recruitment. Unlike BAM depletion, the absence of microglia impairs hypercapnia-induced vasodilation, while in vivo two-photon imaging reveals microglial IL-1α-dependent interactions between leukocytes and penetrating arteries. Accordingly, reduced hypercapnia-induced vasodilation involves endothelial IL-1R1 and microglial IL-1α. Thus, distinct brain macrophage populations exert opposite effects on leukocyte recruitment and CBF through IL-1 dependent mechanisms in given vascular beds in male mice. How brain myeloid cells regulate vascular responses in systemic inflammation is unclear. Here, the authors identify distinct roles for microglia and border-associated macrophages in leukocyte recruitment and cerebral blood flow regulation via IL-1.