Macrophages cFLIP out Pathogens have evolved to survive within hosts in part by interfering with host signaling cascades. Yersinia bacteria use the effector protein YopJ to thwart MAP kinase signaling downstream of Toll-like receptor activation. In response to YopJ, host cells can release interleukin-1β and initiate pyroptosis by inhibition of the kinase TAK1 and subsequent caspase-8–directed cleavage of gasdermin D, a protein that forms cell membrane pores. Muendlein et al. report that cFLIP, a major antiapoptotic regulator, plays a central role in this process. Knockdowns of the long but not short cFLIP isoform in macrophages removes the requirement for TAK1 inhibition. Rather, deficiency of the long isoform fuels caspase-8 activation, mitochondrial complex II formation, pyroptosis, and interleukin-1β secretion in response to lipopolysaccharide alone, underscoring its importance for cell death and inflammation. Science, this issue p. 1379 During inflammation, an anti-apoptotic regulator isoform regulates pyroptosis and interleukin-1β release. 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 cFLIPL promotes complex II formation, driving pyroptosis, and the secretion of IL-1β in response to LPS alone.

中文翻译：

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cFLIPL 通过抑制复合物 II 的形成保护巨噬细胞免受 LPS 诱导的细胞焦亡

巨噬细胞 cFLIP out 病原体已经进化到能够在宿主内生存，部分原因是干扰宿主信号级联。耶尔森氏菌使用效应蛋白 YopJ 来阻止 Toll 样受体激活下游的 MAP 激酶信号传导。作为对 YopJ 的响应，宿主细胞可以释放白细胞介素 1β 并通过抑制激酶 TAK1 和随后的 caspase-8 定向裂解 gasdermin D（一种形成细胞膜孔的蛋白质）来启动细胞焦亡。Muendlein 等人。据报道，cFLIP 是一种主要的抗凋亡调节剂，在该过程中起着核心作用。敲除巨噬细胞中长但不短的 cFLIP 异构体消除了对 TAK1 抑制的要求。相反，长异构体的缺乏会促进 caspase-8 激活、线粒体复合物 II 形成、细胞焦亡、和白细胞介素-1β 分泌仅响应脂多糖，强调了其对细胞死亡和炎症的重要性。科学，这个问题 p。1379 在炎症期间，一种抗凋亡调节异构体可调节细胞焦亡和白细胞介素 1β 的释放。细胞死亡和炎症是相互依赖的宿主对感染的反应。在细胞焦亡过程中，白细胞介素 1β (IL-1β) 通过 caspase-1 和 caspase-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 分泌。然而，在体外，小鼠巨噬细胞需要第二个“危险信号”来促进炎症小体驱动的 IL-1β 成熟。最近的报告表明，在 LPS 激活的巨噬细胞中，caspase-8 介导的细胞焦亡，但提供了关于在这些条件下释放 IL-1β 的相互矛盾的证据。这里，为了进一步表征体外 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。具体而言，我们表明长同种型 cFLIPL 的缺乏会促进复合物 II 的形成，驱动细胞焦亡，以及单独响应 LPS 的 IL-1β 分泌。