Blocking GSDMD processing in innate immune cells but not in hepatocytes protects hepatic ischemia-reperfusion injury
Blocking GSDMD processing in innate immune cells but not in hepatocytes protects hepatic ischemia-reperfusion injury
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阻断先天免疫细胞而非肝细胞中的 GSDMD 处理可保护肝脏缺血再灌注损伤
DOI：
10.1038/s41419-020-2437-9
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发表时间：
2020-04-17
影响因子：
9
通讯作者：
Kong, Xiaoni
中科院分区：
文献类型：
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作者：
Li, Jichang;Zhao, Jie;Kong, Xiaoni
细胞凋亡是细胞程序性死亡的一种促炎形式，在许多疾病的发病机制中起重要作用。在肝脏缺血再灌注损伤（IRI）中发现的炎性小体激活与肝细胞凋亡密切相关，提示肝细胞凋亡可能在肝脏IRI中发生并发挥作用。然而，没有直接证据表明焦亡在肝IRI中的作用。在本研究中，通过检测肝细胞凋亡标志物，我们发现肝细胞凋亡可能在肝IRI过程中被诱导。此外，通过采用caspase-1抑制剂，我们发现抑制肝细胞凋亡可以显著减轻肝损伤，抑制肝脏IRI时的炎症反应。有趣的是，caspase-1抑制剂对缺氧/复氧条件下的体外肝细胞没有保护作用。为了研究其中特定细胞类型可能影响肝IRI的诱导的焦亡，我们产生肝细胞特异性Gsdmd敲除（Hep-Gsdmd（-/-））和骨髓特异性Gsdmd敲除（LysmCre（+）Gsdmd（f/f））小鼠。功能实验表明，与对照组（Gsdmd（f/f））相比，LysmCre（+）Gsdmd（f/f）小鼠的肝损伤和炎症减轻，而AlbCre（+）Gsdmd（f/f）小鼠的肝损伤和炎症没有减轻。在平行的体外研究中，与对照组相比，LysmCre（+）Gsdmd（f/f）小鼠骨髓源性巨噬细胞和枯否细胞中细胞因子的表达和产生减少。我们的研究结果表明，先天免疫细胞的热凋亡加剧了肝脏IRI，提示通过阻断热凋亡可以保护肝脏IRI，这可能成为临床上潜在的治疗靶点。
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 (LysmCre(+)Gsdmd(f/f)) mice. Functional experiments showed that compared to control mice (Gsdmd(f/f)), there were alleviated liver injury and inflammation in LysmCre(+)Gsdmd(f/f) mice, but not in AlbCre(+)Gsdmd(f/f) mice. In parallel in vitro studies, cytokine expression and production decreased in bone-marrow-derived macrophages and Kupffer cells from LysmCre(+)Gsdmd(f/f) 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.