cFLIPL protects macrophages from LPS-induced pyroptosis via inhibition of complex II formation

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Science  20 Mar 2020:
Vol. 367, Issue 6484, pp. 1379-1384
DOI: 10.1126/science.aay3878

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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


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.

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