The transcription factor T-bet promotes the pathogenesis of nonalcoholic fatty liver disease by upregulating intrahepatic inflammation.
The transcription factor T-bet promotes the pathogenesis of nonalcoholic fatty liver disease by upregulating intrahepatic inflammation.
复制标题
DOI：
10.1016/j.bbrc.2023.10.014
复制
发表时间：
2023-10
影响因子：
3.1
通讯作者：
Guangyong Sun;Yunxiong Wei;Jingjing Zhu;Shimeng Zheng;Zihan Zhang;Dong Zhang
中科院分区：
文献类型：
--
作者：
Guangyong Sun;Yunxiong Wei;Jingjing Zhu;Shimeng Zheng;Zihan Zhang;Dong Zhang
目的探讨转录因子T-bet在非酒精性脂肪性肝病(NAFLD)发病机制中的作用及对肝内免疫微环境的调节作用。通过组织化学染色观察T-bet基因敲除在NAFLD发病机制中的作用。用流式细胞仪检测T-bet在肝脏免疫细胞中的表达，以及T-bet基因敲除对肝脏免疫细胞亚群比例和功能的影响。结果流式细胞仪检测结果显示，NAFLD小鼠肝脏免疫细胞，尤其是NKT细胞中T-bet表达增加。敲除转录因子T-bet可减轻肝内炎症反应，减少脂质堆积，改善NAFLD的发病机制。根据免疫细胞亚群分析，敲除转录因子T-bet降低了非酒精性脂肪肝小鼠肝脏中NK、NKT和CD8T细胞的比例、存活率和活化程度，并减少了T细胞和NKT细胞分泌干扰素-γ，但对Th17T细胞和Treg细胞的比例没有影响。敲除转录因子T-bet还可降低NAFLD肝脏中促炎症髓系衍生巨噬细胞(MoMFs)的比例，主要是促炎症Ly6ChighMoMFs的比例。此外，敲除转录因子T-bet对巨噬细胞分泌肿瘤坏死因子-α无明显影响，但显著降低MHC-II类分子的表达。进一步分析表明，转录因子T-bet可能通过转录调控直接影响MHC-II类分子H2-AB1和H2-Dmb1的表达。结论敲除转录因子T-bet可降低NAFLD肝脏固有免疫细胞(MoMFs、NK细胞和NKT细胞)和T淋巴细胞的促炎作用，从而减轻肝内炎症，延缓NAFLD的发病。
ObjectiveTo investigate the effect of the transcription factor T-bet on the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the regulation of the intrahepatic immune microenvironment.MethodsWild-type and T-bet knockout NASH mouse models were constructed. The effect of T-bet knockout on the pathogenesis of NAFLD was observed by histochemical staining. The expression of T-bet in immune cells in the liver and the effect of T-bet knockout on the proportion and function of immune cell subsets in the liver were determined by flow analysis.ResultsFlow cytometry results indicated that T-bet expression was increased in immune cells, especially NKT cells, in the livers of NAFLD mice. Knocking out the transcription factor T-bet reduced intrahepatic inflammation, reduced lipid accumulation, and ameliorated the pathogenesis of NAFLD. Based on the analysis of immune cell subsets, knocking out the transcription factor T-bet decreased the proportion, survival, and degree of activation of NK, NKT, and CD8 T cells in NAFLD liver; additionally, it decreased the secretion of IFN-γ by T cells and NKT cells but had no effect on the proportion of Th17 cells and Treg cells. Knocking out the transcription factor T-bet also reduced the proportion of proinflammatory myeloid-derived macrophages (MoMFs) in NAFLD liver, mainly the proportion of proinflammatory Ly6ChighMoMFs. Furthermore, knocking out the transcription factor T-bet had no significant effect on the secretion of TNF-α from MoMFs but significantly reduced the expression of MHC class II molecules. Further analysis showed that the transcription factor T-bet may directly affect the expression of MHC class II moleculesH2-AB1andH2-Dmb1through transcriptional regulation.ConclusionsKnocking out the transcription factor T-bet reduced the proinflammatory effect of innate immune cells (MoMFs, NK cells, and NKT cells) and T lymphocytes in NAFLD liver, thereby reducing intrahepatic inflammation and delaying the pathogenesis of NAFLD.