The cleavage of gasdermin D by caspase-11 promotes tubular epithelial cell pyroptosis and urinary IL-18 excretion in acute kidney injury
The cleavage of gasdermin D by caspase-11 promotes tubular epithelial cell pyroptosis and urinary IL-18 excretion in acute kidney injury
复制标题
Caspase-11对gasdermin D的裂解促进急性肾损伤中肾小管上皮细胞焦亡和尿IL-18排泄
DOI：
10.1016/j.kint.2019.04.035
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发表时间：
2019-11-01
影响因子：
19.6
通讯作者：
Lu, Limin
中科院分区：
文献类型：
--
作者：
Miao, Naijun;Yin, Fan;Lu, Limin
炎症和肾小管细胞死亡是急性肾损伤的标志。然而，这些影响的确切机制尚未完全阐明。在这里，我们测试了 caspase-11（Caspase 家族的炎症成员）在顺铂或缺血再灌注诱导的急性肾损伤中是否增加。 Caspase-11 敲除小鼠经顺铂治疗后表现出肾功能恶化减弱、肾小管损伤减少、巨噬细胞和中性粒细胞浸润减少以及尿 IL-18 排泄减少。从机制上讲，顺铂或缺血再灌注使 caspase-11 上调，将gasdermin D (GSDMD) 裂解为 GSDMD-N，后者易位到质膜上，从而触发细胞焦亡并促进原代培养的肾小管细胞中 IL-18 的释放。这些结果在 GSDMD 敲除小鼠中得到进一步证实，顺铂诱导的肾脏形态和功能恶化以及尿 IL-18 排泄得到缓解。此外，GSDMD 的缺乏显着抑制顺铂诱导的 IL-18 释放，但不抑制肾小管细胞中 IL-18 的转录和成熟水平。因此，我们的研究表明，caspase-11/GSDMD 依赖性肾小管细胞焦亡在急性肾损伤中引发肾小管细胞损伤、尿 IL-18 排泄和肾功能恶化中发挥着重要作用。
Inflammation and tubular cell death are the hallmarks of acute kidney injury. However, the precise mechanism underlying these effects has not been fully elucidated. Here we tested whether caspase-11, an inflammatory member of the caspase family, was increased in cisplatin or ischemia-reperfusion-induced acute kidney injury. Caspase-11 knockout mice after cisplatin treatment exhibited attenuated deterioration of renal functional, reduced tubular damage, reduced macrophage and neutrophil infiltration, and decreased urinary IL-18 excretion. Mechanistically, the upregulation of caspase-11 by either cisplatin or ischemia-reperfusion cleaved gasdermin D (GSDMD) into GSDMD-N, which translocated onto the plasma membrane, thus triggering cell pyroptosis and facilitated IL-18 release in primary cultured renal tubular cells. These results were further confirmed in GSDMD knockout mice that cisplatin-induced renal morphological and functional deterioration as well as urinary IL-18 excretion were alleviated. Furthermore, deficiency of GSDMD significantly suppressed cisplatin-induced IL-18 release but not the transcription and maturation level of IL-18 in tubular cells. Thus, our study indicates that caspase-11/GSDMD dependent tubule cell pyroptosis plays a significant role in initiating tubular cell damage, urinary IL-18 excretion and renal functional deterioration in acute kidney injury.