Wright Skylar S, Kumari Puja, Fraile-Ágreda Víctor, Wang Chengliang, Shivcharan Sonia, Kappelhoff Shirin, Margheritis Eleonora G, Matz Alyssa, Vasudevan Swathy O, Rubio Ignacio, Bauer Michael, Zhou Beiyan, Vanaja Sivapriya Kailasan, Cosentino Katia, Ruan Jianbin, Rathinam Vijay A
Department of Immunology, UConn Health School of Medicine, 263 Farmington Avenue, Farmington, CT 06030, USA.
Department of Immunology, UConn Health School of Medicine, 263 Farmington Avenue, Farmington, CT 06030, USA; Department of Biological Sciences, Binghamton University, Binghamton, NY 13902, USA.
Cell. 2025 Jan 23;188(2):280-291.e17. doi: 10.1016/j.cell.2024.11.018. Epub 2024 Dec 31.
Pyroptosis mediated by gasdermins (GSDMs) plays crucial roles in infection and inflammation. Pyroptosis triggers the release of inflammatory molecules, including damage-associated molecular patterns (DAMPs). However, the consequences of pyroptosis-especially beyond interleukin (IL)-1 cytokines and DAMPs-that govern inflammation are poorly defined. Here, we show intercellular propagation of pyroptosis from dying cells to bystander cells in vitro and in vivo. We identified extracellular vesicles (EVs) released by pyroptotic cells as the propagator of lytic death to naive cells, promoting inflammation. DNA-PAINT super-resolution and immunoelectron microscopy revealed GSDMD pore structures on EVs released by pyroptotic cells. Importantly, pyroptotic EVs transplant GSDMD pores on the plasma membrane of bystander cells and kill them. Overall, we demonstrate that cell-to-cell vesicular transplantation of GSDMD pores disseminates pyroptosis, revealing a domino-like effect governing disease-associated bystander cell death.
由gasdermin（GSDM）介导的细胞焦亡在感染和炎症中起关键作用。细胞焦亡触发包括损伤相关分子模式（DAMP）在内的炎症分子的释放。然而，细胞焦亡的后果——尤其是除白细胞介素（IL）-1细胞因子和DAMP之外——对炎症的影响尚不清楚。在这里，我们展示了细胞焦亡在体外和体内从垂死细胞向旁观者细胞的细胞间传播。我们确定焦亡细胞释放的细胞外囊泡（EV）是将溶解性死亡传播给未成熟细胞、促进炎症的介质。DNA-PAINT超分辨率和免疫电子显微镜揭示了焦亡细胞释放的EV上存在GSDMD孔结构。重要的是，焦亡EV将GSDMD孔移植到旁观者细胞的质膜上并杀死它们。总体而言，我们证明GSDMD孔的细胞间囊泡移植传播了细胞焦亡，揭示了一种类似多米诺骨牌效应的机制，控制与疾病相关的旁观者细胞死亡。
