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 Ly6Clo monocytes. Mechanistically, Rbpj deficiency promoted lipid uptake driven by elevated CD36 expression in Ly6Clo 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.

中文翻译：

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Notch 信号转导调节代谢功能障碍相关脂肪性肝病中巨噬细胞介导的炎症


肝脏巨噬细胞群包括常驻库普弗细胞 （KC） 和单核细胞衍生的巨噬细胞，这些巨噬细胞具有不同的促炎或抗炎特性，会影响肝病的严重程度和病程。代谢功能障碍相关脂肪性肝病和/或脂肪性肝炎 （MASLD/MASH） 中巨噬细胞分化和功能的机制仍然大多未知。使用单细胞 RNA 测序 （scRNA-seq） 和肝脏巨噬细胞亚群的命运图谱，我们揭示了 MASH 中不同单核细胞和单核细胞衍生的巨噬细胞亚群的时间和空间动力学。我们揭示了免疫球蛋白 kappa J 区 （RBPJ） 信号通路的 Notch-Recombination 信号结合蛋白在控制单核细胞到巨噬细胞转变中的关键作用，Rbpj 缺陷减弱了炎性巨噬细胞和单核细胞衍生的 KC 分化，反而促进了保护性 Ly6Clo 单核细胞的出现。从机制上讲，Rbpj 缺陷促进了 Ly6Clo 单核细胞中 CD36 表达升高驱动的脂质摄取，增强了它们与内皮细胞的保护性相互作用。我们的研究结果揭示了 Notch-RBPJ 信号在单核细胞到巨噬细胞转化中的关键作用，并将有助于设计 MASH 治疗的治疗策略。