Interleukin-34-dependent perivascular macrophages promote vascular function in the brain

The development of most macrophages depends on the colony-stimulating factor 1 (CSF-1) receptor, which has two ligands: CSF-1 and interleukin-34 (IL-34). While IL-34 is required for the homeostasis of microglia, the parenchymal macrophages in the central nervous system (CNS), it is unclear whether brain border-associated macrophages (BAMs) also depend on this cytokine. Here, we demonstrated that the embryonic development of murine BAMs in the choroid plexus, leptomeninges, and perivascular spaces required CSF-1, while IL-34 was critical for their maintenance in adulthood. In the brain, Il34 was expressed by mural cells and perivascular fibroblasts, and its transgenic deletion in these cells interrupted BAM maintenance. Il34-deficiency coincided with transcriptional changes in vascular cells, leading to increased flow velocity and vasomotion in pial and penetrating arterioles. Similarly, Mrc1CreCsf1rfl/fl mice lacking CD206+ perivascular BAMs exhibited increased hemodynamics in arterial networks. These findings reveal a crosstalk between vascular cells and CNS macrophages regulating cerebrovascular function. Overall design: scRNA-seq of FACS-sorted mural cells (MCs) and fibroblasts (FBs) (CD13+ and/or CD140a+O4- cells), endothelial cells (ECs) (CD31+), astrocytes (AC) (ACSA-2+), BAMs (CD11bhiF4/80+) and microglia (CD11b+F4/80hi) from adult Mrc1CreCsf1rfl/fl and Csf1rfl/fl mice.