Pyroptotic cell corpses are crowned with F-actin-rich filopodia that engage CLEC9A signaling in incoming dendritic cells
While apoptosis dismantles the cell to enforce immunological silence, pyroptotic cell death provokes inflammation. Little is known of the structural architecture of cells undergoing pyroptosis, and whether pyroptotic corpses are immunogenic. Here we report that inflammasomes trigger the Gasdermin-D- and calcium-dependent eruption of filopodia from the plasma membrane minutes before pyroptotic cell rupture, to crown the resultant corpse with filopodia. As a rich store of F-actin, pyroptotic filopodia are recognized by dendritic cells through the F-actin receptor, CLEC9A (DNGR1). We propose that cells assemble filopodia before cell rupture to serve as a posthumous mark for a cell that has died by gasdermin-induced pyroptosis, or MLKL-induced necroptosis, for recognition by dendritic cells. This study reveals the spectacular morphology of pyroptosis and identifies a mechanism by which inflammasomes induce pyroptotic cells to construct a de novo alarmin that activates dendritic cells via CLEC9A, which coordinates the transition from innate to adaptive immunity<sup>1,2</sup>.
Authors
- Robert J. Ju (ORCID: https://orcid.org/0000-0002-9850-9803)
- Stefan Emming (ORCID: https://orcid.org/0000-0002-3851-335X)
- Samantha J. Stehbens (ORCID: https://orcid.org/0000-0002-8145-2708)
- Mireille H. Lahoud (ORCID: https://orcid.org/0000-0001-8472-6201)
- Sabrina Sofia Burgener (ORCID: https://orcid.org/0000-0002-9332-7998)
- Alpha S. Yap (ORCID: https://orcid.org/0000-0002-1038-8956)
- James Lefevre (ORCID: https://orcid.org/0000-0002-5945-9575)
- Kate Schroder (ORCID: https://orcid.org/0000-0001-9261-3805)
- Mercedes Monteleone (ORCID: https://orcid.org/0000-0003-0777-3965)
- Daniel Fisch (ORCID: https://orcid.org/0000-0002-8155-0367)
- Caroline L. Holley (ORCID: https://orcid.org/0000-0002-2231-0136)
- Grace Lawrence (ORCID: https://orcid.org/0000-0001-9764-1194)
- Nicholas Ariotti (ORCID: https://orcid.org/0000-0003-3901-0831)
- Joanna Crawford (ORCID: https://orcid.org/0000-0003-0786-6889)
- Nicholas D. Condon (ORCID: https://orcid.org/0000-0002-1833-1129)
- Nicholas Hamilton (ORCID: https://orcid.org/0000-0003-0331-3427)
- Rinie Bajracharya (ORCID: https://orcid.org/0000-0002-5629-5309)
- Jonathan C. Kagan (ORCID: https://orcid.org/0000-0003-2364-2746)
- Joon H. Choi (ORCID: https://orcid.org/0000-0003-4254-0286)
- J. Coombs (ORCID: https://orcid.org/0000-0002-1703-1247)
- A Libert (ORCID: https://orcid.org/0009-0005-7299-2672)
Institutions
- Boston Children's Hospital (US)
- Harvard University (US)
- The University of Queensland (AU)
- Max Planck Institute for Infection Biology (DE)
- Monash University (AU)
Publication Details
- Journal
- Nature Immunology
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1038/s41590-024-02024-3
- Citations
- 23
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 5.38
Funders
- Silicon Valley Community Foundation
- European Molecular Biology Organization
- Novartis Foundation
- Human Frontier Science Program
- University of Queensland
- National Institutes of Health
- Australian Research Council
- National Health and Medical Research Council