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^1,2,3,4. 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 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.

细胞焦亡是一种溶解性细胞死亡模式，有助于限制感染的传播，也与无菌炎症性疾病和自身免疫性疾病的病理有关 ^1,2,3,4 。在焦亡过程中，炎症小体激活和 caspase-1 结合导致细胞死亡，同时炎症细胞因子白细胞介素 1β (IL-1β) 成熟和分泌。 IL-1β 在促进组织炎症方面的主导作用掩盖了焦亡细胞释放的其他因子的潜在影响。在这里，使用诱导巨噬细胞发生细胞焦亡而不释放 IL-1β 或 IL-1α 的系统（表示为 Pyro ⁻¹ ），我们发现了 Pyro ⁻¹ 分泌组的意想不到的有益作用。首先，我们注意到 Pyro ⁻¹ 上清液上调了与迁移、细胞增殖和伤口愈合相关的基因特征。与该基因特征一致，Pyro ⁻¹ 上清液促进原代成纤维细胞和巨噬细胞的迁移，并促进体外伤口更快闭合并改善体内组织修复。在机制研究中，Pyro ⁻¹ 上清液的脂质组学和代谢组学鉴定了氧脂质和代谢物的存在，将它们与促进伤口愈合的作用联系起来。特别关注氧脂素前列腺素 E ₂ (PGE ₂ )，我们发现其合成是在细胞焦亡过程中从头诱导的，位于 caspase-1 激活和环氧合酶-2 活性的下游；此外，PGE ₂ 合成发生在细胞焦亡后期，其释放依赖于细胞焦亡期间打开的gasdermin D 孔。至于焦亡代谢物，它们与免疫细胞浸润到伤口以及 CD301 ⁺ 巨噬细胞的极化有关。 总的来说，这些数据提出了这样的概念：焦亡分泌蛋白组具有具有组织修复特性的氧脂质和代谢物，可用于治疗。