Molecular mechanisms of liver injury, repair, and immunity

肝脏是天然免疫力较强的器官，在宿主抵御微生物感染和肿瘤转化中发挥着重要作用。新的证据表明，先天性免疫以及由先天性免疫细胞产生的各种细胞因子也参与了急慢性肝病的发病机制。我们实验室一直在积极研究先天免疫及其相关细胞因子在肝脏损伤和修复中的作用。在本财政年度，我们已经证明了脂肪组织相关巨噬细胞在肝脏损伤和炎症的发病机制中发挥了重要作用。 我们已经证明，脂肪细胞死亡通过激活趋化因子(C-C基序)受体2阳性的巨噬细胞和脂解作用，优先诱导肝脏损伤和炎症。摘要：脂肪细胞死亡发生在各种生理病理条件下，包括肥胖和饮酒，并可引发器官损害，特别是肝脏，但其潜在机制仍不清楚。为了探索这些机制，我们建立了一种通过在脂肪细胞上过表达人CD59(HCD59)来诱导脂肪细胞死亡的小鼠模型(脂肪细胞特异性hCD59转基因小鼠)。这些小鼠注射中间溶素(ILY)，通过与hCD59结合而不是与小鼠CD59结合，迅速特异性地溶解表达hCD59的细胞，导致脂肪细胞急性选择性死亡，脂肪巨噬细胞浸润，血清游离脂肪酸(FFA)水平升高。注射LID还可导致多器官的继发性损伤，其中以肝脏损伤最严重，并伴有炎症和肝巨噬细胞活化。机制上，急性脂肪细胞死亡以趋化因子(C-C基序)受体2阳性(CCR2+)巨噬细胞依赖的方式增加脂肪组织中肾上腺素和去甲肾上腺素水平，激活脂肪分解途径，随后肝脏中FFA释放和脂毒性。此外，急性脂肪细胞死亡导致肝脏CCR2+巨噬细胞活化和浸润，进一步加重肝脏损伤。结论：脂肪细胞死亡主要导致肝脏损伤和炎症，这可能是由于肝细胞对脂肪毒性的高度敏感性和肝脏内巨噬细胞的丰富所致。

The liver is an organ with strong innate immunity, which plays an important role in host defense against microbial infection and tumor transformation. Emerging evidence suggests that innate immunity as well as a variety of cytokines produced by innate immune cells also contribute to the pathogenesis of acute and chronic liver diseases. Our laboratory has been actively studying the role of innate immunity and its associated cytokines in liver injury and repair. During the fiscal year, we have demonstrated that adipose tissues-associated macrophages play an important role in the pathogenesis of liver injury and inflammation. We have demonstrated that adipocyte death preferentially induces liver injury and inflammation through the activation of chemokine (C-C Motif) receptor 2-positive macrophages and lipolysis. Abstract: Adipocyte death occurs under various physiopathological conditions, including obesity and alcohol drinking, and can trigger organ damage particularly in the liver, but the underlying mechanisms remain obscure. To explore these mechanisms, we developed a mouse model of inducible adipocyte death by overexpressing the human CD59 (hCD59) on adipocytes (adipocyte-specific hCD59 transgenic mice). Injection of these mice with intermedilysin (ILY), which rapidly lyses hCD59 expressing cells exclusively by binding to the hCD59 but not mouse CD59, resulted in the acute selective death of adipocytes, adipose macrophage infiltration, and elevation of serum free fatty acid (FFA) levels. ILY injection also resulted in the secondary damage to multiple organs with the strongest injury observed in the liver, with inflammation and hepatic macrophage activation. Mechanistically, acute adipocyte death elevated epinephrine and norepinephrine levels and activated lipolysis pathways in adipose tissue in a chemokine (C-C motif) receptor 2-positive (CCR2+ ) macrophage-dependent manner, which was followed by FFA release and lipotoxicity in the liver. Additionally, acute adipocyte death caused hepatic CCR2+ macrophage activation and infiltration, further exacerbating liver injury. Conclusion: Adipocyte death predominantly induces liver injury and inflammation, which is probably due to the superior sensitivity of hepatocytes to lipotoxicity and the abundance of macrophages in the liver.