Gao Wei, Wang Yufen, Bi Jian, Chen Xiuli, Li Na, Wang Yingde, Tang Haiying, Mao Jingwei
Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Department of GI Endoscopy, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Biochem Biophys Res Commun. 2021 Jan 1;534:34-40. doi: 10.1016/j.bbrc.2020.12.007. Epub 2020 Dec 10.
Abnormal crosstalk between gut immune and the liver was involved in nonalcoholic steatohepatitis (NASH). Mice with methionine choline-deficient (MCD) diet-induced NASH presented an imbalance of pro-(IL-6 and IFN-γ) and anti-inflammatory cytokines (IL-10) in the intestine. We also clarified that the ratio of CD4 T cells and found that the NASH mesenteric lymph node (MLN) presents decreased numbers of CD4Th17 cells but increased numbers of CD4CD8FoxP3 regulatory T cells (Tregs). Furthermore, the intestinal immune imbalance in NASH was attributed to impaired gut chemokine receptor 9 (CCR9)/chemokine ligand 25 (CCL25) signalling, which is a crucial pathway for immune cell homing in the gut. We also demonstrated that CD4CCR9 T cell homing was dependent on CCL25 and that the numbers and migration abilities of CD4CCR9 T cells were reduced in NASH. Interestingly, the analysis of dendritic cell (DC) subsets showed that the numbers and retinal dehydrogenase (RALDH) activity of CD103CD11b DCs were decreased and that the ability of these cells to upregulate CD4 T cell CCR9 expression was damaged in NASH. Taken together, impaired intestinal CCR9/CCL25 signalling induced by CD103CD11b DC dysfunction contributes to the gut immune imbalance observed in NASH.
肠道免疫与肝脏之间的异常串扰参与了非酒精性脂肪性肝炎（NASH）的发生。采用蛋氨酸胆碱缺乏（MCD）饮食诱导NASH的小鼠肠道中促炎细胞因子（白细胞介素6和干扰素γ）和抗炎细胞因子（白细胞介素10）失衡。我们还明确了CD4 T细胞的比例，发现NASH肠系膜淋巴结（MLN）中CD4Th17细胞数量减少，但CD4CD8FoxP3调节性T细胞（Tregs）数量增加。此外，NASH中的肠道免疫失衡归因于肠道趋化因子受体9（CCR9）/趋化因子配体25（CCL25）信号受损，这是免疫细胞在肠道归巢的关键途径。我们还证明CD4CCR9 T细胞归巢依赖于CCL25，且NASH中CD4CCR9 T细胞的数量和迁移能力降低。有趣的是，树突状细胞（DC）亚群分析显示，NASH中CD103CD11b DC的数量和视黄醛脱氢酶（RALDH）活性降低，且这些细胞上调CD4 T细胞CCR9表达的能力受损。综上所述，由CD103CD11b DC功能障碍诱导的肠道CCR9/CCL25信号受损导致了NASH中观察到的肠道免疫失衡。
