Graduate Program in Genetics, Tufts Graduate School of Biomedical Sciences, Boston, MA 02111, USA.
Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, MA 02111, USA.
Science. 2020 Mar 20;367(6484):1379-1384. doi: 10.1126/science.aay3878.
Cell death and inflammation are interdependent host responses to infection. During pyroptotic cell death, interleukin-1β (IL-1β) release occurs through caspase-1 and caspase-11-mediated gasdermin D pore formation. In vivo, responses to lipopolysaccharide (LPS) result in IL-1β secretion. In vitro, however, murine macrophages require a second "danger signal" for the inflammasome-driven maturation of IL-1β. Recent reports have shown caspase-8-mediated pyroptosis in LPS-activated macrophages but have provided conflicting evidence regarding the release of IL-1β under these conditions. Here, to further characterize the mechanism of LPS-induced secretion in vitro, we reveal an important role for cellular FLICE-like inhibitory protein (cFLIP) in the regulation of the inflammatory response. Specifically, we show that deficiency of the long isoform cFLIP promotes complex II formation, driving pyroptosis, and the secretion of IL-1β in response to LPS alone.
细胞死亡和炎症是宿主对感染的相互依存的反应。在细胞焦亡性细胞死亡过程中，白细胞介素-1β（IL-1β）通过半胱天冬酶-1 和半胱天冬酶-11 介导的 gasdermin D 孔形成释放。在体内，对脂多糖（LPS）的反应导致 IL-1β 的分泌。然而，在体外，鼠巨噬细胞需要第二种“危险信号”来驱动 IL-1β 的炎性体成熟。最近的报道显示，LPS 激活的巨噬细胞中存在 caspase-8 介导的细胞焦亡，但在这些条件下释放 IL-1β 的证据相互矛盾。在这里，为了进一步阐明体外 LPS 诱导分泌的机制，我们揭示了细胞 FLICE 样抑制蛋白（cFLIP）在调节炎症反应中的重要作用。具体来说，我们表明长型 cFLIP 的缺乏促进了复合物 II 的形成，从而驱动仅 LPS 刺激下的细胞焦亡和 IL-1β 的分泌。
