Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
Sci Immunol. 2023 Sep 29;8(87):eadd1599. doi: 10.1126/sciimmunol.add1599.
Metabolic-associated fatty liver disease (MAFLD) is a spectrum of clinical manifestations ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of nonalcoholic steatohepatitis (NASH), which can potentially lead to fibrosis and hepatocellular carcinoma, but the triggers of MAFLD-associated inflammation are not well understood. We have observed that lipid accumulation in hepatocytes induces expression of ligands specific to the activating immune receptor NKG2D. Tissue-resident innate-like T cells, most notably γδ T cells, are activated through NKG2D and secrete IL-17A. IL-17A licenses hepatocytes to produce chemokines that recruit proinflammatory cells into the liver, which causes NASH and fibrosis. NKG2D-deficient mice did not develop fibrosis in dietary models of NASH and had a decreased incidence of hepatic tumors. The frequency of IL-17A γδ T cells in the blood of patients with MAFLD correlated directly with liver pathology. Our findings identify a key molecular mechanism through which stressed hepatocytes trigger inflammation in the context of MAFLD.
代谢相关性脂肪性肝病（MAFLD）是一种临床表现谱，从良性脂肪变性到肝硬化不等。MAFLD 病理生理学的一个关键事件是发生非酒精性脂肪性肝炎（NASH），这可能导致纤维化和肝细胞癌，但 MAFLD 相关炎症的触发因素尚不清楚。我们观察到，肝细胞中的脂质积累会诱导激活免疫受体 NKG2D 的特异性配体表达。组织驻留的固有样 T 细胞，尤其是 γδ T 细胞，通过 NKG2D 被激活，并分泌 IL-17A。IL-17A 使肝细胞产生趋化因子，将促炎细胞招募到肝脏，从而导致 NASH 和纤维化。在 NASH 的饮食模型中，缺乏 NKG2D 的小鼠不会发生纤维化，且肝脏肿瘤的发生率也降低。MAFLD 患者血液中 IL-17A γδ T 细胞的频率与肝病理直接相关。我们的研究结果确定了一个关键的分子机制，即应激肝细胞在 MAFLD 背景下触发炎症。
