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

Brás, Ana Rita and Lénárt, Nikolett and Levard, Damien and Glavan, Martina and Menyhárt, Ákos and Cserép, Csaba and Pósfai, Balázs and Császár, Eszter and Samawar, Sai K. Reddy and Pridans, Clare and Vivien, Denis and Farkas, Eszter and Sorokin, Lydia and Rubio, Marina and Dénes, Ádám (2026) Microglia and border-associated macrophages play opposite roles in cerebrovascular and leukocyte responses under systemic inflammation in male mice. NATURE COMMUNICATIONS. ISSN 2041-1723

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Abstract

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.

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