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. 2025 Jan 23;188(2):280-291.e17.
doi: 10.1016/j.cell.2024.11.018. Epub 2024 Dec 31.

Transplantation of gasdermin pores by extracellular vesicles propagates pyroptosis to bystander cells

Skylar S Wright  1 , Puja Kumari  2 , Víctor Fraile-Ágreda  3 , Chengliang Wang  1 , Sonia Shivcharan  1 , Shirin Kappelhoff  4 , Eleonora G Margheritis  4 , Alyssa Matz  1 , Swathy O Vasudevan  1 , Ignacio Rubio  5 , Michael Bauer  5 , Beiyan Zhou  1 , Sivapriya Kailasan Vanaja  1 , Katia Cosentino  4 , Jianbin Ruan  1 , Vijay A Rathinam  6
Affiliations

Transplantation of gasdermin pores by extracellular vesicles propagates pyroptosis to bystander cells

Skylar S Wright et al. Cell. .

Abstract

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.

Keywords: GSDMD; bystander; caspase-1; caspase-11; gasdermin; inflammasomes; pyroptosis; sepsis.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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