Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany.
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany.
Cell Rep. 2017 Dec 26;21(13):3846-3859. doi: 10.1016/j.celrep.2017.12.018.
Inflammasomes activate the protease caspase-1, which cleaves interleukin-1β and interleukin-18 to generate the mature cytokines and controls their secretion and a form of inflammatory cell death called pyroptosis. By generating mice expressing enzymatically inactive caspase-1, we provide genetic evidence that caspase-1 protease activity is required for canonical IL-1 secretion, pyroptosis, and inflammasome-mediated immunity. In caspase-1-deficient cells, caspase-8 can be activated at the inflammasome. Using mice either lacking the pyroptosis effector gasdermin D (GSDMD) or expressing caspase-1, we found that GSDMD-dependent pyroptosis prevented caspase-8 activation at the inflammasome. In the absence of GSDMD-dependent pyroptosis, the inflammasome engaged a delayed, alternative form of lytic cell death that was accompanied by the release of large amounts of mature IL-1 and contributed to host protection. Features of this cell death modality distinguished it from apoptosis, suggesting it may represent a distinct form of pro-inflammatory regulated necrosis.
炎症小体激活蛋白酶半胱天冬酶-1，后者将白细胞介素-1β 和白细胞介素-18 切割成成熟细胞因子，并控制其分泌和一种称为细胞焦亡的炎症细胞死亡形式。通过生成表达酶失活半胱天冬酶-1 的小鼠，我们提供了遗传证据，证明半胱天冬酶-1 蛋白酶活性是经典白细胞介素-1 分泌、细胞焦亡和炎症小体介导的免疫所必需的。在缺乏半胱天冬酶-1 的细胞中，半胱天冬酶-8 可以在炎症小体处被激活。使用缺乏细胞焦亡效应蛋白 GSDMD（Gasdermin D）或表达半胱天冬酶-1 的小鼠，我们发现 GSDMD 依赖性细胞焦亡可防止半胱天冬酶-8 在炎症小体处被激活。在缺乏 GSDMD 依赖性细胞焦亡的情况下，炎症小体参与了一种延迟的、替代形式的裂解性细胞死亡，伴随着大量成熟白细胞介素-1 的释放，并有助于宿主保护。这种细胞死亡模式的特征使其与细胞凋亡区分开来，提示它可能代表一种不同形式的促炎调节性坏死。
