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

Summary

Pyroptotic cells release extracellular vesicles carrying GSDMD pores that insert into bystander cell membranes and induce lytic death, propagating inflammation. Using DNA-PAINT and immuno-EM, the study structurally visualizes GSDMD pores on EVs and demonstrates intercellular propagation of pyroptosis in vitro and in vivo.

Key Findings

• Extracellular vesicles from pyroptotic cells carry GSDMD pore structures visualized by DNA-PAINT and immunoelectron microscopy.
• Pyroptotic EVs transplant GSDMD pores onto bystander cell membranes, inducing lytic death and amplifying inflammation.
• Intercellular propagation of pyroptosis was demonstrated both in vitro and in vivo, revealing a domino-like spread mechanism.

Clinical Implications

Targeting EV release, cargo loading, or GSDMD pore assembly could mitigate bystander tissue injury in infections and sepsis. The findings also motivate biomarker development based on EV-associated GSDMD.

Limitations

• Preclinical models may not capture the full complexity of human sepsis and tissue microenvironments
• Therapeutic blockade of EV-mediated pore transfer was not evaluated for efficacy

Future Directions

Test pharmacologic or genetic inhibition of EV biogenesis/cargo loading or GSDMD pore assembly in infection models, and explore EV-associated GSDMD as a circulating biomarker.