上海交通大学Florent Ginhoux等研究人员合作发现，Notch信号通路调控代谢功能障碍相关脂肪肝疾病中的巨噬细胞介导的炎症。这一研究成果于2024年9月23日在线发表在国际学术期刊《免疫》上。

研究人员表示，肝脏巨噬细胞群体由常驻的库普弗细胞（KC）和单核细胞来源的巨噬细胞组成，它们具有不同的促炎或抗炎特性，影响肝病的严重程度和进程。代谢功能障碍相关脂肪肝疾病和/或脂肪性肝炎（MASLD/MASH）中巨噬细胞分化和功能的机制仍大部分未知。

通过单细胞RNA测序（scRNA-seq）和肝脏巨噬细胞亚群的命运追踪，研究人员揭示了MASH中不同单核细胞及其衍生巨噬细胞亚群的时间和空间动态。研究人员发现Notch-重组信号结合蛋白J区（RBPJ）信号通路在控制单核细胞向巨噬细胞转变中发挥了关键作用，Rbpj缺失抑制了炎症巨噬细胞和单核细胞来源KC的分化，同时促进了保护性Ly6C^lo单核细胞的出现。

在机制上，Rbpj缺失促进了Ly6C^lo单核细胞中CD36表达升高所驱动的脂质摄取，增强了其与内皮细胞的保护性相互作用。该研究揭示了Notch-RBPJ信号在单核细胞向巨噬细胞转变中的关键作用，将有助于设计MASH治疗的策略。

附：英文原文

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

Author: Wei Guo, Ziyi Li, Gerasimos Anagnostopoulos, Wan Ting Kong, Shuangyan Zhang, Svetoslav Chakarov, Amanda Shin, Jiawen Qian, Yiwen Zhu, Wenjuan Bai, Olivier Cexus, Binen Nie, Jing Wang, Xiaoyu Hu, Camille Blériot, Zhaoyuan Liu, Baiyong Shen, Nicolas Venteclef, Bing Su, Florent Ginhoux

Issue&Volume: 2024-09-23

Abstract: 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.

DOI: 10.1016/j.immuni.2024.08.016

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00414-X