比利时根特大学Kodi S. Ravichandran团队发现，来自嗜热细胞的氧脂素和代谢物是组织修复的促进剂。这一研究成果于2024年6月26日在线发表在国际学术期刊《自然》上。

研究人员表示，焦亡是一种溶解性细胞死亡模式，有助于限制感染的传播，也与无菌性炎症疾病和自身免疫性疾病的病理有关。在焦亡过程中，炎性小体激活和caspase-1参与导致细胞死亡，同时炎性细胞因子白细胞介素-1β（IL-1β）成熟并分泌。IL-1β在促进组织炎症方面的主导作用，使人们对焦亡细胞释放的其他因子的潜在影响产生了怀疑。

因此，研究人员使用了一种不释放IL-1β或IL-1α的巨噬细胞诱导系统（称为Pyro-1），发现了Pyro-1分泌组意想不到的有益作用。首先，研究人员注意到Pyro-1上清液上调了与迁移、细胞增殖和伤口愈合有关的基因特征。与这种基因特征相一致的是，Pyro-1上清液促进了原代成纤维细胞和巨噬细胞的迁移，在体外促进了伤口的快速闭合，在体内改善了组织修复。在机理研究中，Pyro-1上清液的脂质组学和代谢组学发现了氧脂素和代谢物的存在，并将它们与促进伤口愈合的作用联系起来。

研究人员特别关注氧脂素前列腺素E₂（PGE₂），发现它的合成是在焦亡过程中，在caspase-1激活和环氧合酶-2活性的下游从头开始诱导的；此外，PGE₂的合成发生在焦亡后期，其释放依赖于焦亡过程中打开的gasdermin D孔。至于裂解代谢产物，它们与免疫细胞渗入伤口并极化为CD301⁺巨噬细胞有关。总之，这些数据推进了这样一个概念，即焦亡分泌组具有可用于治疗的具有组织修复特性的氧脂素和代谢物。

附：英文原文

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

Author: Mehrotra, Parul, Maschalidi, Sophia, Boeckaerts, Laura, Mauerder, Christian, Tixeira, Rochelle, Pinney, Jonathan, Burgoa Cards, Javier, Sukhov, Vladimir, Incik, Yunus, Anderson, Christopher. J., Hu, Bing, Keeli, Burcu N., Goncalves, Amanda, Vande Walle, Lieselotte, Van Opdenbosch, Nina, Sergushichev, Alexey, Hoste, Esther, Jain, Umang, Lamkanfi, Mohamed, Ravichandran, Kodi S.

Issue&Volume: 2024-06-26

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 diseases1,2,3,4. 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 Pyro1), we identify unexpected beneficial effects of the Pyro1 secretome. First, we noted that the Pyro1 supernatants upregulated gene signatures linked to migration, cellular proliferation and wound healing. Consistent with this gene signature, Pyro1 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 Pyro1 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.

DOI: 10.1038/s41586-024-07585-9

Source: https://www.nature.com/articles/s41586-024-07585-9