San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.
Front Immunol. 2022 Jul 1;13:898298. doi: 10.3389/fimmu.2022.898298. eCollection 2022.
Gasdermins (GSDMs) are a class of pore-forming proteins related to pyroptosis, a programmed cell death pathway that is induced by a range of inflammatory stimuli. Small-scale GSDM activation and pore formation allow the passive release of cytokines, such as IL-1β and IL-18, and alarmins, but, whenever numerous GSDM pores are assembled, osmotic lysis and cell death occur. Such GSDM-mediated pyroptosis promotes pathogen clearance and can help restore homeostasis, but recent studies have revealed that dysregulated pyroptosis is at the root of many inflammation-mediated disease conditions. Moreover, new homeostatic functions for gasdermins are beginning to be revealed. Here, we review the newly discovered mechanisms of GSDM activation and their prominent roles in host defense and human diseases associated with chronic inflammation. We also highlight the potential of targeting GSDMs as a new therapeutic approach to combat chronic inflammatory diseases and cancer and how we might overcome the current obstacles to realize this potential.
Gasdermins (GSDMs) 是一类与细胞焦亡相关的成孔蛋白，细胞焦亡是一种由多种炎症刺激诱导的程序性细胞死亡途径。小范围的 GSDM 激活和孔形成允许细胞因子（如 IL-1β 和 IL-18）和警报素的被动释放，但当大量 GSDM 孔组装时，会发生渗透裂解和细胞死亡。这种 GSDM 介导的细胞焦亡有助于清除病原体，并有助于恢复体内平衡，但最近的研究表明，细胞焦亡的失调是许多炎症介导的疾病的根源。此外，gasdermins 的新的体内平衡功能开始被揭示。在这里，我们综述了 GSDM 激活的新发现机制及其在宿主防御和与慢性炎症相关的人类疾病中的突出作用。我们还强调了靶向 GSDMs 作为治疗慢性炎症性疾病和癌症的新方法的潜力，以及我们如何克服当前的障碍来实现这一潜力。
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