College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, China; Department of Cell Metabolism and Nutrition, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
Department of Cell Metabolism and Nutrition, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan; Institute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015, China.
Metabolism. 2022 Nov;136:155272. doi: 10.1016/j.metabol.2022.155272. Epub 2022 Jul 29.
Chemokine (C-X3-C motif) ligand 1 (CX3CL1) and its receptor CX3CR1 regulate the migration and activation of immune cells and are involved in the pathogenesis of nonalcoholic steatohepatitis (NASH), but the mechanism remains elusive. Here, the roles of CX3CL1/CX3CR1 in the macrophage migration and polarization in the livers of NASH mice were investigated.
The expression of Cx3cl1 and Cx3cr1 was markedly upregulated in the livers of lipotoxicity-induced NASH mice. CX3CR1 was predominantly expressed by F4/80 macrophages and to a lesser degree by hepatic stellate cells or endothelial cells in the livers of NASH mice. Flow cytometry analysis revealed that, compared with chow-fed mice, NASH mice exhibited a significant increase in CX3CR1 expression by liver macrophages (LMs), particularly M1 LMs. CX3CR1 deficiency caused a significant increase in inflammatory monocyte/macrophage infiltration and a shift toward M1 dominant macrophages in the liver, thereby exacerbating the progression of NASH. Moreover, transplantation of Cx3cr1 bone marrow was sufficient to cause glucose intolerance, inflammation, and fibrosis in the liver. In addition, deletion of CCL2 in Cx3cr1 mice alleviated NASH progression by decreasing macrophage infiltration and inducing a shift toward M2 dominant LMs. Importantly, overexpression of CX3CL1 in vivo protected against hepatic fibrosis in NASH.
Pharmacological therapy targeting liver CX3CL1/CX3CR1 signaling might be a candidate for the treatment of NASH.
趋化因子（C-X3-C 基序）配体 1（CX3CL1）及其受体 CX3CR1 调节免疫细胞的迁移和激活，并参与非酒精性脂肪性肝炎（NASH）的发病机制，但具体机制仍不清楚。本研究旨在探讨 CX3CL1/CX3CR1 在 NASH 小鼠肝脏中巨噬细胞迁移和极化中的作用。
脂毒性诱导的 NASH 小鼠肝脏中 Cx3cl1 和 Cx3cr1 的表达明显上调。在 NASH 小鼠的肝脏中，CX3CR1 主要表达于 F4/80 巨噬细胞，其次是肝星状细胞或内皮细胞。流式细胞术分析显示，与正常饮食喂养的小鼠相比，NASH 小鼠肝脏巨噬细胞（LMs），尤其是 M1 型 LMs，CX3CR1 的表达显著增加。CX3CR1 缺失导致炎症性单核细胞/巨噬细胞浸润显著增加，肝脏中向 M1 型巨噬细胞优势极化，从而加重 NASH 的进展。此外，Cx3cr1 骨髓移植足以导致肝脏葡萄糖不耐受、炎症和纤维化。此外，在 Cx3cr1 小鼠中缺失 CCL2 可通过减少巨噬细胞浸润和诱导 M2 型 LMs 优势极化来减轻 NASH 进展。重要的是，体内过表达 CX3CL1 可防止 NASH 中的肝纤维化。
靶向肝脏 CX3CL1/CX3CR1 信号的药物治疗可能是治疗 NASH 的候选方法。
