Résumé
The liver macrophage population comprises resident Kupffer cells (KCs) and recruited monocytederived macrophages. Monocytes are mostly recruited during liver inflammation and can differentiate into several types of macrophages with distinct pro-or anti-inflammatory properties that affect the severity and course of liver diseases. The mechanisms that underlie macrophage differentiation and function in nonalcoholic steatohepatitis (NASH) remain mostly unknown. Here, using single-cell RNA sequencing, fate mapping, intra-vital imaging and conditional knock-out mouse models of hepatic macrophage subpopulations, we unraveled the temporal and spatial dynamics of distinct monocyte and monocyte-derived macrophage subsets in NASH. We uncovered a crucial role for the Notch-RBPJ signaling pathway in controlling the recruitment, differentiation, localization, and functions of liver macrophages in NASH. Notch-RBPJ signaling controls the monocyte-to-macrophage transition in vivo, with Rbpj deficiency blunting inflammatory macrophage and long-lived MoKC differentiation and conversely promoting the emergence of Nr4a1-dependent protective Ly6C lo monocytes. Mechanistically, absence of Rbpj promoted stronger lipid uptake driven by elevated CD36 expression in KCs and Ly6C lo monocytes, enhancing their protective interactions with endothelial cells. Our findings uncovered the crucial role of Notch-RBPJ signaling in liver monocyte-to-macrophage transition, identified new cellular targets and will aid the design of novel therapeutic strategies for the treatment of NASH.