Diabetes Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; ITMO University, Saint Petersburg, Russia.
Cell Rep. 2021 Jan 12;34(2):108626. doi: 10.1016/j.celrep.2020.108626.
Macrophage-mediated inflammation is critical in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we describe that, with high-fat, high-sucrose-diet feeding, mature TIM4 Kupffer cells (KCs) decrease in number, while monocyte-derived Tim4 macrophages accumulate. In concert, monocyte-derived infiltrating macrophages enter the liver and consist of a transitional subset that expresses Cx3cr1/Ccr2 and a second subset characterized by expression of Trem2, Cd63, Cd9, and Gpmnb; markers ascribed to lipid-associated macrophages (LAMs). The Cx3cr1/Ccr2-expressing macrophages, referred to as C-LAMs, localize to macrophage aggregates and hepatic crown-like structures (hCLSs) in the steatotic liver. In C-motif chemokine receptor 2 (Ccr2)-deficient mice, C-LAMs fail to appear in the liver, and this prevents hCLS formation, reduces LAM numbers, and increases liver fibrosis. Taken together, our data reveal dynamic changes in liver macrophage subsets during the pathogenesis of NASH and link these shifts to pathologic tissue remodeling.
巨噬细胞介导的炎症在非酒精性脂肪性肝炎（NASH）的发病机制中至关重要。在这里，我们描述了在高脂肪、高蔗糖饮食喂养下，成熟的 TIM4 库普弗细胞（KCs）数量减少，而单核细胞衍生的 Tim4 巨噬细胞积累。与此同时，单核细胞衍生的浸润性巨噬细胞进入肝脏，并由表达 Cx3cr1/Ccr2 的过渡亚群和以表达 Trem2、Cd63、Cd9 和 Gpmnb 为特征的第二个亚群组成；这些标志物被归为与脂质相关的巨噬细胞（LAMs）。表达 Cx3cr1/Ccr2 的巨噬细胞，称为 C-LAMs，定位于脂肪变性肝脏中的巨噬细胞聚集和肝冠状样结构（hCLS）。在 C 基序趋化因子受体 2（Ccr2）缺陷小鼠中，C-LAMs 未能出现在肝脏中，这阻止了 hCLS 的形成，减少了 LAM 数量，并增加了肝纤维化。总之，我们的数据揭示了 NASH 发病机制中肝巨噬细胞亚群的动态变化，并将这些变化与病理性组织重塑联系起来。
