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. The authors thank Pál Vági of the Light Microscopy Center at the HUN-REN Institute of Experimental Medicine, Hungary for kindly providing microscopy support. We also thank the Medical Gene Technology Unit and the Cell Biology Center at the HUN-REN Institute of Experimental Medicine for their support.

The authors are grateful to Plexxikon for providing PLX5622 for these studies. The authors are grateful to Clare Pridans for providing us with the CSF1RΔFIRE/ΔFIRE mice. This work was supported with funding from the ERC-CoG 724994 (A.

Denes), the “Momentum” Program of the Hungarian Academy of Sciences (LP2016- 4/2016 to A. Denes) and the Hungarian Brain Research Program KTIA_13_NAP-A-I/ 2(A. This project has also received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant “ENTRAIN” agreement no. 813294 (A.R.

Sorokin was supported by the ERC-2021-ADG 101054805 - B3MN. Denes were supported by the ERA-NET 2024 MeniSPYs. Menyhárt was supported by grants from the National Research, Development and Innovation Office of Hungary (NKFIH STARTING_24 (No. 150356) and FK142218).