Monocyte-derived IL-6 Programs Microglia to Rebuild Damaged Brain Vasculature

Cerebrovascular injury (CVI) is a common pathology caused by infections, injury, stroke, neurodegeneration, and autoimmune disease. Rapid resolution of a CVI requires a coordinated innate immune response. In this study, we sought mechanistic insights into how CNS infiltrating monocytes program resident microglia to mediate angiogenesis and cerebrovascular repair following intracerebral hemorrhage. In the penumbrae of human stroke brain lesions, we identified a subpopulation of microglia that express VEGFA. These cells, termed repair associated microglia (RAM), were also observed in a rodent model of CVI and co-expressed IL-6Ra. Cerebrovascular repair did not occur in IL-6 knockouts or in mice lacking microglial IL-6Ra expression, and single cell transcriptomic analyses revealed faulty RAM programming in the absence of IL-6 signaling. Infiltrating CCR2+ monocytes were the primary source of IL-6 following CVI and were required to endow microglia with proliferative and pro-angiogenic properties. Faulty RAM programming in the absence of IL-6 or inflammatory monocytes resulted in poor cerebrovascular repair, neuronal destruction, and sustained neurological deficits that were all restored via exogenous IL-6 administration. These data provide a molecular and cellular basis for how monocytes instruct microglia to repair damaged brain vasculature and promote functional recovery after injury. Overall design: Brain samples from 4 different mice representing Sham injury (Ctrl) under IL-6 WT (+/+) condition (S1), Cerebrovascular injury (CVI) under IL-6 WT (+/+) condition (S2), Sham injury (Ctrl) under IL-6 KO (-/-) condition (S3), and Cerebrovascular injury (CVI) under IL-6 KO (-/-) condition (S4) were analyzed by scRNAseq.