IL-10 prevents pathological microglia hyperactivation following peripheral endotoxin challenge

Microglia, the resident macrophages of the brain parenchyma, are central players in CNS development, homeostasis and disorders. Distinct brain pathologies seem associated with discrete microglia activation modules. How microglia regain their ground state following challenges remains much less understood. Here, we explored the role of the IL-10 axis in restoring murine microglia homeostasis following peripheral endotoxin challenge. Specifically, we show that lipopolysaccharide (LPS)-challenged mice harboring IL-10 receptor-deficient microglia display neuronal impairment and succumb to fatal sickness. Addition of a microglial TNF deficiency rescues these animals, suggesting a microglia-based circuit driving pathology. Single cell transcriptome analysis revealed various IL-10 producing resident and recruited immune cell in the CNS, including most prominently Ly49D+ NK cells and neutrophils, but not microglia. Collectively, we define the kinetics of the microglia response to peripheral endotoxin challenge, including their activation and robust silencing, and highlight the critical role of non-microglial IL-10 in preventing deleterious microglia hyperactivation. sample of LPS treated whole brain + dura, sample of LPS treated whole brain + dura, sample of WT whole brain + dura