CX3CL1/CX3CR1 interaction protects against lipotoxicity-induced nonalcoholic steatohepatitis by regulating macrophage migration and M1/M2 status
CX3CL1/CX3CR1 interaction protects against lipotoxicity-induced nonalcoholic steatohepatitis by regulating macrophage migration and M1/M2 status
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DOI：
10.1016/j.metabol.2022.155272
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发表时间：
2022-08-23
影响因子：
9.8
通讯作者：
Nagashimada, Mayumi
中科院分区：
文献类型：
--
作者：
Ni, Yinhua;Fen Zhuge;Nagashimada, Mayumi
背景和目标：趋化因子（C-X3-C motif）配体1（CX 3CL 1）及其受体CX 3CR 1调节免疫细胞的迁移和活化，参与非酒精性脂肪性肝炎（NASH）的发病机制，但其机制尚不清楚。在这里，CX 3CL 1/CX 3CR 1在巨噬细胞的迁移和极化在NASH小鼠livers.Methods和结果的作用：Cx 3CL 1和Cx 3CR 1的表达显着上调，在肝脏中的脂毒性诱导的NASH小鼠。在NASH小鼠肝脏中，CX 3CR 1主要由F4/80+巨噬细胞表达，并且在较小程度上由肝星状细胞或内皮细胞表达。流式细胞术分析显示，与普通饲料喂养的小鼠相比，NASH小鼠表现出肝脏巨噬细胞（LM），特别是M1 LM的CX 3CR 1+表达显著增加。CX 3CR 1缺乏导致炎症性单核细胞/巨噬细胞浸润显著增加，并使肝脏中的巨噬细胞向M1优势转移，从而加剧NASH的进展。此外，移植Cx 3cr 1-/-骨髓足以引起葡萄糖耐受不良、炎症和肝纤维化。此外，Cx 3cr 1-/-小鼠中CCL 2的缺失通过减少巨噬细胞浸润和诱导向M2主导LM的转变来减轻NASH进展。结论：以肝脏CX 3CL 1/CX 3CR 1信号通路为靶点的药物治疗可能成为治疗NASH的一种新方法。
Background and objectives: 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.Methods and results: 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 exacer-bating 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.Conclusion: Pharmacological therapy targeting liver CX3CL1/CX3CR1 signaling might be a candidate for the treatment of NASH.