Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Central Laboratory, Department of Liver Diseases, Institute of Clinical Immunology, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China.
Cell Death Dis. 2020 Apr 17;11(4):244. doi: 10.1038/s41419-020-2437-9.
Pyroptosis, a proinflammatory form of programmed cell death, plays important roles in the pathogenesis of many diseases. Inflammasome activation, which has been shown in hepatic ischemia-reperfusion injury (IRI), is demonstrated to be closely associated with pyroptosis, indicating that pyroptosis may occur and perform functions in hepatic IRI. However, there is no direct evidence showing the function of pyroptosis in hepatic IRI. In this study, by detecting the pyroptosis markers, we showed that pyroptosis may be induced during hepatic IRI. Furthermore, by adopting caspase-1 inhibitors, we showed that inhibition of pyroptosis could significantly ameliorate liver injury and suppress inflammatory response during hepatic IRI. Interestingly, caspase-1 inhibitors have no protective effects on in vitro hepatocytes under hypoxic reoxygenation condition. To investigate pyroptosis induced in which specific cell types may affect hepatic IRI, we generated hepatocyte-specific Gsdmd-knockout (Hep-Gsdmd) and myeloid-specific Gsdmd-knockout (LysmCreGsdmd) mice. Functional experiments showed that compared to control mice (Gsdmd), there were alleviated liver injury and inflammation in LysmCreGsdmd mice, but not in AlbCreGsdmd mice. In parallel in vitro studies, cytokine expression and production decreased in bone-marrow-derived macrophages and Kupffer cells from LysmCreGsdmd mice compared to their controls. Our findings demonstrated that pyroptosis in innate immune cells aggravates hepatic IRI and implied that hepatic IRI could be protected by blocking pyroptosis, which may become a potential therapeutic target in the clinic.
细胞焦亡是一种促炎形式的程序性细胞死亡，在许多疾病的发病机制中发挥重要作用。炎症小体的激活已在肝缺血再灌注损伤（IRI）中得到证实，与细胞焦亡密切相关，表明细胞焦亡可能在肝 IRI 中发生并发挥作用。然而，尚无直接证据表明细胞焦亡在肝 IRI 中的作用。在本研究中，通过检测细胞焦亡标志物，我们表明细胞焦亡可能在肝 IRI 期间被诱导。此外，通过采用半胱天冬酶-1 抑制剂，我们表明抑制细胞焦亡可显著改善肝损伤并抑制肝 IRI 期间的炎症反应。有趣的是，半胱天冬酶-1 抑制剂在体外低氧复氧条件下对肝细胞没有保护作用。为了研究在何种特定细胞类型中诱导的细胞焦亡可能影响肝 IRI，我们生成了肝细胞特异性 Gsdmd 敲除（Hep-Gsdmd）和髓样细胞特异性 Gsdmd 敲除（LysmCreGsdmd）小鼠。功能实验表明，与对照小鼠（Gsdmd）相比，LysmCreGsdmd 小鼠的肝损伤和炎症减轻，但 AlbCreGsdmd 小鼠则没有。平行的体外研究表明，与对照相比，LysmCreGsdmd 小鼠的骨髓源性巨噬细胞和枯否细胞中的细胞因子表达和产生减少。我们的研究结果表明，固有免疫细胞中的细胞焦亡加重了肝 IRI，并暗示通过阻断细胞焦亡可以保护肝 IRI，这可能成为临床中的一个潜在治疗靶点。
