He Wei, Xu Jin, Wang Xiang, Fan Zhining, Li Hai
Department of Gastroenterology, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Institute, Jiangsu Province Official Hospital, Nanjing, 210024, Jiangsu Province, China.
Heliyon. 2024 Jul 25;10(15):e35197. doi: 10.1016/j.heliyon.2024.e35197. eCollection 2024 Aug 15.
Previous studies have shown that pyroptosis in hepatocyte is essential for the development of MAFLD. Growing evidence has shown that exosomal miRNAs-mediated communication between inflammatory cells and hepatocyte is an important link in MAFLD. In the present study, we aim to elucidate whether macrophage-derived exosomal miRNAs contribute to the hepatocyte pyroptosis in the pathophysiological process of MAFLD.
The effects of hepatocyte pyroptosis were investigated in an HFD-induced MAFLD mouse model and in the liver tissues from patients with MAFLD using immunohistochemistry, real-time PCR, Western blotting, and luciferase reporter assay, among other techniques. MiR-155 inhibitor tail injections and AAV-FoxO3a-GFP were also administered to respectively inhibit or overexpress its expression in an HFD-induced MAFLD mouse model.
Hepatocyte pyroptosis was heightened in the liver tissue of patients with MAFLD or HFD-induced MAFLD mouse. Importantly, treatment with a caspase-1 inhibitor or overexpression of FoxO3a reversed this trend. Our study also demonstrated that miR-155 expression and the number of infiltrated macrophages were increased, and knockdown of miR-155 attenuated hepotocyte pyroptosis and liver fibrosis in HFD-induced mouse. In addition, we demonstrated that macrophage-derived exosomal miR-155 was transferred to hepatocytes, leading to hepatocyte pyroptosis in MAFLD mouse. Furthermore, blockade of exosome secretion improved hepotocyte pyroptosis and liver fibrosis in HFD-induced mouse. On the contrary, macrophage-derived exosomal miR-155 worsened hepotocyte pyroptosis. Moreover, we found that miR-155 promoted hepatocyte pyroptosis in MAFLD by down-regulating FoxO3a.
Taken together, our results demonstrated that macrophage-derived exosomal miR-155 promotes hepatocyte pyroptosis and liver fibrosis in MAFLD.
先前的研究表明，肝细胞焦亡在MAFLD的发展中至关重要。越来越多的证据表明，外泌体miRNA介导的炎症细胞与肝细胞之间的通讯是MAFLD的重要环节。在本研究中，我们旨在阐明巨噬细胞衍生的外泌体miRNA是否在MAFLD的病理生理过程中促进肝细胞焦亡。
使用免疫组织化学、实时PCR、蛋白质印迹和荧光素酶报告基因检测等技术，在高脂饮食诱导的MAFLD小鼠模型和MAFLD患者的肝组织中研究肝细胞焦亡的影响。还对高脂饮食诱导的MAFLD小鼠模型进行尾静脉注射miR-155抑制剂和AAV-FoxO3a-GFP，分别抑制或过表达其表达。
MAFLD患者或高脂饮食诱导的MAFLD小鼠的肝组织中肝细胞焦亡加剧。重要的是，用caspase-1抑制剂治疗或过表达FoxO3a可逆转这一趋势。我们的研究还表明，miR-155表达和浸润巨噬细胞数量增加，敲低miR-155可减轻高脂饮食诱导小鼠的肝细胞焦亡和肝纤维化。此外，我们证明巨噬细胞衍生的外泌体miR-155转移至肝细胞，导致MAFLD小鼠肝细胞焦亡。此外，阻断外泌体分泌可改善高脂饮食诱导小鼠的肝细胞焦亡和肝纤维化。相反，巨噬细胞衍生的外泌体miR-155会加重肝细胞焦亡。此外，我们发现miR-155通过下调FoxO3a促进MAFLD中的肝细胞焦亡。
综上所述，我们的结果表明，巨噬细胞衍生的外泌体miR-155促进MAFLD中的肝细胞焦亡和肝纤维化。
