Wu Meng, Sun Jing, Wang Li, Wang Peiwen, Xiao Tian, Wang Suhua, Liu Qizhan
Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute of Public Health, Gusu School, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute of Public Health, Gusu School, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Department of Nutrition, Functional Food Clinical Evaluation Center, Affiliated Hospital of Jiangnan University, Wuxi 214122, Jiangsu, People's Republic of China.
J Hazard Mater. 2023 Feb 5;443(Pt B):130276. doi: 10.1016/j.jhazmat.2022.130276. Epub 2022 Oct 29.
Arsenic compounds are toxins that are widely distributed in the environment. Chronic exposure to low levels of these compounds can cause hepatic fibrosis and other damage. Th17 differentiation of CD4 T cells and the secretion of IL-17 activates hepatic stellate cells (HSCs), which are involved in hepatic fibrosis, but their mechanisms in arsenic-induced hepatic fibrosis are unclear. We found, in arsenite-induced fibrotic livers of mice, increases of CD4 T cell infiltration, Th17 cell nuclear receptor retinoic acid receptor-related orphan receptor γt (RORγt), and secretion of the pro-inflammatory cytokine IL-17. There were also elevated levels of the lncRNA, HOTAIR. For Jurkat cells, arsenite elevated levels of HOTAIR and protein levels of RORγt and IL-17A, decreased miR-17-5p, promoted Th17 cell differentiation, and released IL-17. The culture medium of arsenite-treated Jurkat cells activated LX-2 cells. Down-regulation of HOTAIR or up-regulation of miR-17-5p blocked arsenite-induced Th17 cell differentiation, which inhibited the LX-2 cell activation. However, down-regulation of HOTAIR and miR-17-5p reversed this inhibitory effect. For mice, silencing of HOTAIR diminished the hepatic levels of RORγt and IL-17A and alleviated arsenite-induced hepatic fibrosis. These results demonstrate that, for CD4 T cells, arsenite promotes RORγt-mediated Th17 cell differentiation through HOTAIR down-regulation of miR-17-5p, and increases the secretion of cytokine IL-17A, which activates HSCs; the activated HSCs facilitate hepatic fibrosis. The findings reveal a new mechanism and a potential therapeutic target for arsenite-induced hepatic fibrosis.
砷化合物是广泛分布于环境中的毒素。长期低水平接触这些化合物会导致肝纤维化和其他损害。CD4 T细胞的Th17分化以及IL-17的分泌会激活参与肝纤维化的肝星状细胞（HSCs），但其在砷诱导的肝纤维化中的机制尚不清楚。我们发现，在亚砷酸盐诱导的小鼠纤维化肝脏中，CD4 T细胞浸润增加、Th17细胞核受体视黄酸受体相关孤儿受体γt（RORγt）增加以及促炎细胞因子IL-17的分泌增加。lncRNA HOTAIR的水平也升高。对于Jurkat细胞，亚砷酸盐提高了HOTAIR的水平以及RORγt和IL-17A的蛋白水平，降低了miR-17-5p，促进了Th17细胞分化，并释放了IL-17。亚砷酸盐处理的Jurkat细胞的培养基激活了LX-2细胞。HOTAIR的下调或miR-17-5p的上调阻断了亚砷酸盐诱导的Th17细胞分化，从而抑制了LX-2细胞的激活。然而，HOTAIR和miR-17-5p的下调逆转了这种抑制作用。对于小鼠，HOTAIR的沉默降低了肝脏中RORγt和IL-17A的水平，并减轻了亚砷酸盐诱导的肝纤维化。这些结果表明，对于CD4 T细胞，亚砷酸盐通过HOTAIR下调miR-17-5p促进RORγt介导的Th17细胞分化，并增加细胞因子IL-17A分泌，从而激活HSCs；被激活的HSCs促进肝纤维化。这些发现揭示了亚砷酸盐诱导肝纤维化的新机制和潜在治疗靶点。
