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

• 成果类型: Article
• 署名作者: Mehrotra, Parul; Maschalidi, Sophia; Boeckaerts, Laura; Maueroder, Christian; Tixeira, Rochelle; Pinney, Jonathan; Cardas, Javier Burgoa; Sukhov, Vladimir; Incik, Yunus; Anderson, Christopher. J.; Hu, Bing; Keceli, Burcu N.; Goncalves, Amanda; Vande Walle, Lieselotte; Van Opdenbosch, Nina; Sergushichev, Alexey; Hoste, Esther; Jain, Umang; Lamkanfi, Mohamed; Ravichandran, Kodi S.
• 署名单位: Ghent University; Flanders Institute for Biotechnology (VIB); Ghent University; Indian Institute of Technology System (IIT System); Indian Institute of Technology (IIT) - Delhi; University of Virginia; ITMO University; Washington University (WUSTL); Flanders Institute for Biotechnology (VIB); Ghent University; Washington University (WUSTL)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4269
• DOI: 10.1038/s41586-024-07585-9
• 发表日期: 2024-07-04
• 关键词: nlrp3 inflammasome; aim2 inflammasome; gene-expression; gasdermin d; activation; induction; prostaglandin-e2; improves; release; gsdmd

摘要

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-1 beta (IL-1 beta). The dominant effect of IL-1 beta 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-1 beta or IL-1 alpha 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.