Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, 200241, China.
Department of Respiratory and Critical Care Medicine, Changzheng Hospital, Naval Military Medical University, Shanghai, 200003, China.
Cell Death Dis. 2024 Sep 30;15(9):703. doi: 10.1038/s41419-024-07072-z.
Pyroptosis, a typical inflammatory cell death mode, has been increasingly demonstrated to have therapeutic value in inflammatory diseases such as sepsis. However, the mechanisms and therapeutic targets of sepsis remain elusive. Here, we reported that REGγ inhibition promoted pyroptosis by regulating members of the gasdermin family in macrophages. Mechanistically, REGγ directly degraded Bim, a factor of the Bcl-2 family that can inhibit the cleavage of GSDMD/E, ultimately preventing the occurrence of pyroptosis. Furthermore, cecal ligation and puncture (CLP)-induced sepsis model mice showed downregulation of REGγ at both the RNA and protein levels. Gasdermin-mediated pyroptosis was augmented in REGγ-knockout mice, and these mice exhibited more severe sepsis-related tissue injury. More importantly, we found that REGγ expression was downregulated in clinical sepsis samples, such as those from patients with Pseudomonas aeruginosa (PA) infection. Finally, PA-infected mice showed decreased REGγ levels in the lung. In summary, our study reveals that the REGγ-Bim-GSDMD/E pathway is a novel regulatory mechanism of pyroptosis in sepsis-related tissue injury.
细胞焦亡是一种典型的炎症细胞死亡方式，在脓毒症等炎症性疾病中已被证明具有治疗价值。然而，脓毒症的发病机制和治疗靶点仍不明确。本研究报道，REGγ 通过调控巨噬细胞中gasdermin 家族成员的表达促进细胞焦亡。机制上，REGγ 可直接降解 Bcl-2 家族抑制 GSDMD/E 切割的因子 Bim，从而阻止细胞焦亡的发生。此外，盲肠结扎穿孔（CLP）诱导的脓毒症模型小鼠在 RNA 和蛋白水平均表现出 REGγ 的下调。在 REGγ 敲除小鼠中，gasdermin 介导的细胞焦亡增加，这些小鼠表现出更严重的脓毒症相关组织损伤。更为重要的是，我们发现临床脓毒症样本（如铜绿假单胞菌（PA）感染患者）中 REGγ 的表达下调。最后，PA 感染小鼠的肺部 REGγ 水平降低。综上所述，本研究揭示了 REGγ-Bim-GSDMD/E 通路是脓毒症相关组织损伤中细胞焦亡的一种新的调控机制。
