Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair

Parul Mehrotra (), Sophia Maschalidi, Laura Boeckaerts, Christian Maueröder, Rochelle Tixeira, Jonathan Pinney, Javier Burgoa Cardás, Vladimir Sukhov, Yunus Incik, Christopher. J. Anderson, Bing Hu, Burcu N. Keçeli, Amanda Goncalves, Lieselotte Vande Walle, Nina Opdenbosch, Alexey Sergushichev, Esther Hoste, Umang Jain, Mohamed Lamkanfi and Kodi S. Ravichandran ()
Additional contact information
Parul Mehrotra: VIB-UGent Center for Inflammation Research
Sophia Maschalidi: VIB-UGent Center for Inflammation Research
Laura Boeckaerts: VIB-UGent Center for Inflammation Research
Christian Maueröder: VIB-UGent Center for Inflammation Research
Rochelle Tixeira: VIB-UGent Center for Inflammation Research
Jonathan Pinney: University of Virginia
Javier Burgoa Cardás: VIB-UGent Center for Inflammation Research
Vladimir Sukhov: ITMO University
Yunus Incik: VIB-UGent Center for Inflammation Research
Christopher. J. Anderson: VIB-UGent Center for Inflammation Research
Bing Hu: VIB-UGent Center for Inflammation Research
Burcu N. Keçeli: VIB-UGent Center for Inflammation Research
Amanda Goncalves: VIB Bio Imaging Core
Lieselotte Vande Walle: Ghent University
Nina Opdenbosch: Ghent University
Alexey Sergushichev: ITMO University
Esther Hoste: VIB-UGent Center for Inflammation Research
Umang Jain: Washington University School of Medicine
Mohamed Lamkanfi: Ghent University
Kodi S. Ravichandran: VIB-UGent Center for Inflammation Research

Nature, 2024, vol. 631, issue 8019, 207-215

Abstract: Abstract Pyroptosis is a lytic cell death mode that helps limit the spread of infections and is also linked to pathology in sterile inflammatory diseases and autoimmune diseases1–4. During pyroptosis, inflammasome activation and the engagement of caspase-1 lead to cell death, along with the maturation and secretion of the inflammatory cytokine interleukin-1β (IL-1β). The dominant effect of IL-1β in promoting tissue inflammation has clouded the potential influence of other factors released from pyroptotic cells. Here, using a system in which macrophages are induced to undergo pyroptosis without IL-1β or IL-1α release (denoted Pyro−1), we identify unexpected beneficial effects of the Pyro−1 secretome. First, we noted that the Pyro−1 supernatants upregulated gene signatures linked to migration, cellular proliferation and wound healing. Consistent with this gene signature, Pyro−1 supernatants boosted migration of primary fibroblasts and macrophages, and promoted faster wound closure in vitro and improved tissue repair in vivo. In mechanistic studies, lipidomics and metabolomics of the Pyro−1 supernatants identified the presence of both oxylipins and metabolites, linking them to pro-wound-healing effects. Focusing specifically on the oxylipin prostaglandin E2 (PGE2), we find that its synthesis is induced de novo during pyroptosis, downstream of caspase-1 activation and cyclooxygenase-2 activity; further, PGE2 synthesis occurs late in pyroptosis, with its release dependent on gasdermin D pores opened during pyroptosis. As for the pyroptotic metabolites, they link to immune cell infiltration into the wounds, and polarization to CD301+ macrophages. Collectively, these data advance the concept that the pyroptotic secretome possesses oxylipins and metabolites with tissue repair properties that may be harnessed therapeutically.

Date: 2024
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DOI: 10.1038/s41586-024-07585-9

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