@article{01J03RSPPHM9Z3ZXNXPQX21RX9,
  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 diseases. 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. Defining the composition of the secretome of pyroptotic macrophages reveals the involvement of the component factors in wound healing.}},
  author       = {{Mehrotra, Parul and Maschalidi, Sophia and Boeckaerts, Laura and Maueröder, Christian and Tixeira, Rochelle and Pinney, Jonathan and Burgoa, Javier and Sukhov, Vladimir and Incik, Yunus and Anderson, Christopher and Hu, Bing and Keçeli, Burcu Nur and Gonçalves, Amanda and Vande Walle, Lieselotte and Van Opdenbosch, Nina and Sergushichev, Alexey and Hoste, Esther and Jain, Umang and Lamkanfi, Mohamed and Ravichandran, Kodi}},
  issn         = {{0028-0836}},
  journal      = {{NATURE}},
  keywords     = {{NLRP3 INFLAMMASOME,AIM2 INFLAMMASOME,GENE-EXPRESSION,GASDERMIN D,ACTIVATION,INDUCTION,PROSTAGLANDIN-E2,IMPROVES,RELEASE,GSDMD}},
  language     = {{eng}},
  number       = {{8019}},
  pages        = {{207--215}},
  title        = {{Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair}},
  url          = {{http://doi.org/10.1038/s41586-024-07585-9}},
  volume       = {{631}},
  year         = {{2024}},
}

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