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Publication : Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease.

First Author  Guo W Year  2024
Journal  Immunity Volume  57
Issue  10 Pages  2310-2327.e6
PubMed ID  39317200 Mgi Jnum  J:359351
Mgi Id  MGI:7750187 Doi  10.1016/j.immuni.2024.08.016
Citation  Guo W, et al. (2024) Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease. Immunity 57(10):2310-2327.e6
abstractText  The liver macrophage population comprises resident Kupffer cells (KCs) and monocyte-derived macrophages with distinct pro- or anti-inflammatory properties that affect the severity and course of liver diseases. The mechanisms underlying macrophage differentiation and functions in metabolic dysfunction-associated steatotic liver disease and/or steatohepatitis (MASLD/MASH) remain mostly unknown. Using single-cell RNA sequencing (scRNA-seq) and fate mapping of hepatic macrophage subpopulations, we unraveled the temporal and spatial dynamics of distinct monocyte and monocyte-derived macrophage subsets in MASH. We revealed a crucial role for the Notch-Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) signaling pathway in controlling the monocyte-to-macrophage transition, with Rbpj deficiency blunting inflammatory macrophages and monocyte-derived KC differentiation and conversely promoting the emergence of protective Ly6C(lo) monocytes. Mechanistically, Rbpj deficiency promoted lipid uptake driven by elevated CD36 expression in Ly6C(lo) monocytes, enhancing their protective interactions with endothelial cells. Our findings uncover the crucial role of Notch-RBPJ signaling in monocyte-to-macrophage transition and will aid in the design of therapeutic strategies for MASH treatment.
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