■先前的研究表明,肝细胞中的焦亡对于MAFLD的发展至关重要。越来越多的证据表明,外泌体miRNA介导的炎症细胞和肝细胞之间的通讯是MAFLD的重要环节。在本研究中,我们的目的是阐明巨噬细胞来源的外泌体miRNAs是否在MAFLD的病理生理过程中促进肝细胞焦亡。
■使用免疫组织化学在HFD诱导的MAFLD小鼠模型和MAFLD患者的肝组织中研究了肝细胞焦亡的影响,实时PCR,西方印迹,和荧光素酶报告分析,在其他技术中。还施用MiR-155抑制剂尾注射和AAV-FoxO3a-GFP以分别抑制或过表达其在HFD诱导的MAFLD小鼠模型中的表达。
■在MAFLD或HFD诱导的MAFLD小鼠的肝组织中,肝细胞焦亡增加。重要的是,用caspase-1抑制剂或FoxO3a过表达治疗逆转了这一趋势。我们的研究还证明miR-155的表达和浸润巨噬细胞的数量增加,miR-155的敲除可减弱HFD诱导的小鼠肝细胞焦凋亡和肝纤维化。此外,我们证明了巨噬细胞来源的外泌体miR-155被转移到肝细胞,导致MAFLD小鼠肝细胞焦亡。此外,外泌体分泌的阻断改善了HFD诱导的小鼠的肝细胞焦凋亡和肝纤维化。相反,巨噬细胞来源的外泌体miR-155恶化了肝细胞焦亡。此外,我们发现miR-155通过下调FoxO3a促进MAFLD中肝细胞的焦亡.
■放在一起,我们的结果表明,巨噬细胞来源的外泌体miR-155促进MAFLD的肝细胞焦亡和肝纤维化.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: Taken together, our results demonstrated that macrophage-derived exosomal miR-155 promotes hepatocyte pyroptosis and liver fibrosis in MAFLD.