<b>Notch signaling regulates macrophage-mediated inflammation in non-alcoholic steatohepatitis</b>

The liver macrophage population comprises resident Kupffer cells (KCs) and recruited monocyte-derived 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 (MDM) subsets in NASH. We uncovered a crucial role for the Notch-RBPJ signaling pathway in controlling the differentiation, localization, and functions of liver macrophages in NASH. Notch-RBPJ signaling controls the monocyte-to-macrophage transition <i>in vivo</i>, with <i>Rbpj</i> deficiency blunting inflammatory macrophage differentiation and conversely promoting the emergence of <i>Nr4a1</i>-dependent protective Ly6C^lo monocytes. Mechanistically, the absence of <i>Rbpj</i> promoted stronger lipid uptake driven by elevated CD36 expression in KCs and Ly6C^lo monocytes and enhanced 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.

肝巨噬细胞群体由常驻库普弗细胞（Kupffer cells, KCs）和招募型单核细胞源性巨噬细胞（monocyte-derived macrophage, MDM）组成。单核细胞多在肝脏炎症阶段被招募，并可分化为多种具有独特促炎或抗炎特性的巨噬细胞亚型，这些特性直接影响肝脏疾病的严重程度与病程。目前，非酒精性脂肪性肝炎（nonalcoholic steatohepatitis, NASH）中巨噬细胞分化与功能的调控机制仍未完全阐明。本研究借助单细胞RNA测序（single-cell RNA sequencing）、命运图谱（fate mapping）、活体成像（intra-vital imaging）以及肝脏巨噬细胞亚群条件性敲除小鼠模型，阐明了NASH进程中不同单核细胞及单核细胞源性巨噬细胞亚群的时空动态变化规律。我们发现，Notch-RBPJ信号通路在调控NASH中肝巨噬细胞的分化、定位与功能方面发挥关键作用。Notch-RBPJ信号通路在体内调控单核细胞向巨噬细胞的转化：*Rbpj*基因缺陷会削弱炎性巨噬细胞的分化进程，反之则促进*Nr4a1*依赖性的保护性Ly6C^lo单核细胞的产生。从机制层面来看，*Rbpj*的缺失会通过上调CD36的表达，增强库普弗细胞与Ly6C^lo单核细胞的脂质摄取能力，并强化它们与内皮细胞之间的保护性相互作用。本研究揭示了Notch-RBPJ信号通路在肝脏单核细胞向巨噬细胞转化过程中的核心作用，鉴定出全新的细胞靶点，将为开发治疗非酒精性脂肪性肝炎的新型治疗策略提供重要支撑。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于非酒精性脂肪性肝炎（NASH）中Notch-RBPJ信号通路对巨噬细胞介导炎症的调控机制研究。通过单细胞RNA测序和动物模型，发现Notch-RBPJ通路控制单核细胞向巨噬细胞的分化，Rbpj缺陷可抑制炎性巨噬细胞形成并促进保护性单核细胞出现，揭示了CD36介导的脂质摄取增强在其中的作用。这些发现为NASH的治疗提供了新的细胞靶点和理论依据。