CD8+ T cells regulate liver injury in obesity-related nonalcoholic fatty liver disease
CD8+ T cells regulate liver injury in obesity-related nonalcoholic fatty liver disease
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DOI：
10.1152/ajpgi.00040.2019
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发表时间：
2020-02-01
影响因子：
4.5
通讯作者：
Kennedy, Arion J.
中科院分区：
文献类型：
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作者：
Breuer, Denitra A.;Pacheco, Maria Cristina;Kennedy, Arion J.
由于肥胖的流行，非酒精性脂肪性肝炎（NASH）在西方国家有所增加。目前的研究目标是确定浸润肝脏的免疫细胞的类型和功能，以及在NASH中介导其募集和激活的关键因素。我们研究了肥胖和非肥胖NASH条件下CD8(+) T细胞的功能和表型。我们发现患有NASH和肝硬化的肥胖患者肝脏中CD8染色升高，这与α -平滑肌肌动蛋白正相关，α -平滑肌肌动蛋白是肝星状细胞（HSC）激活的标志。与肥胖肝脂肪变性小鼠相比，肥胖和高脂血症NASH小鼠肝脏中的CD8(+) T细胞升高了3.5倍。从这些小鼠中分离的肝脏CD8(+) T细胞表达细胞毒性il -10表达表型，CD8(+) T细胞的耗竭导致肝脏炎症、HSC激活和巨噬细胞积累的显著减少。此外，来自肥胖和高脂血症NASH小鼠的肝脏CD8(+) T细胞在体外和体内活化造血干细胞。有趣的是，在瘦NASH小鼠模型中，CD8(+) T细胞的消耗和敲低并不影响肝脏炎症或HSC激活。我们证明，在肥胖/高脂血症条件下，CD8(+) T细胞是NASH进展的关键调节因子，而在非肥胖条件下，它们在驱动疾病中起最小作用。因此，靶向CD8(+) T细胞的治疗可能是治疗肥胖相关NASH的一种新方法。我们的研究表明，CD8(+) T细胞是主要的肝T细胞群，在肥胖NASH模型中升高，并直接激活肝星状细胞。相反，我们发现来自瘦NASH模型的CD8(+) T细胞不调节NASH相关炎症或星状细胞活化。因此，据我们所知，我们首次证明肝脏CD8(+) T细胞是肥胖相关NASH的关键参与者。
Nonalcoholic steatohepatitis (NASH) has increased in Western countries due to the prevalence of obesity. Current interests are aimed at identifying the type and function of immune cells that infiltrate the liver and key factors responsible for mediating their recruitment and activation in NASH. We investigated the function and phenotype of CD8(+) T cells under obese and nonobese NASH conditions. We found an elevation in CD8 staining in livers from obese human subjects with NASH and cirrhosis that positively correlated with alpha-smooth muscle actin, a marker of hepatic stellate cell (HSC) activation. CD8(+) T cells were elevated 3.5-fold in the livers of obese and hyperlipidemic NASH mice compared with obese hepatic steatosis mice. Isolated hepatic CD8(+) T cells from these mice expressed a cytotoxic IL-10-expressing phenotype, and depletion of CD8(+) T cells led to significant reductions in hepatic inflammation, HSC activation, and macrophage accumulation. Furthermore, hepatic CD8(+) T cells from obese and hyperlipidemic NASH mice activated HSCs in vitro and in vivo. Interestingly, in the lean NASH mouse model, depletion and knockdown of CD8(+) T cells did not impact liver inflammation or HSC activation. We demonstrated that under obese/hyperlipidemia conditions, CD8(+) T cell are key regulators of the progression of NASH, while under nonobese conditions they play a minimal role in driving the disease. Thus, therapies targeting CD8(+) T cells may be a novel approach for treatment of obesity-associated NASH.NEW & NOTEWORTHY Our study demonstrates that CD8(+) T cells are the primary hepatic T cell population, are elevated in obese models of NASH, and directly activate hepatic stellate cells. In contrast, we find CD8(+) T cells from lean NASH models do not regulate NASH-associated inflammation or stellate cell activation. Thus, for the first time to our knowledge, we demonstrate that hepatic CD8(+) T cells are key players in obesity-associated NASH.