cFLIP < sub > S < /sub > regulates alternative NLRP3 inflammasome activation in human monocytes

Cell Mol Immunol. 2023 Aug 17. doi: 10.1038/s41423-023-01077-y. Online ahead of print.ABSTRACTThe innate immune responses, including inflammasome activation, are paramount for host defense against pathogen infection. In contrast to canonical and noncanonical inflammasome activation, in this study, heat-killed gram-negative bacteria (HK bacteria) were identified as single-step stimulators of the NLRP3 inflammasome in human monocytes, and they caused a moderate amount of IL-1β to be released from cells. Time course experiments showed that this alternative inflammasome response was finished within a few hours. Further analysis showed that the intrinsically limited NLRP3 inflammasome activation response was due to the negative regulation of caspase-8 by the short isoform of cFLIP (cFLIPs), which was activated by NF-κB. In contrast, overexpressed cFLIPS, but not overexpressed cFLIPL, inhibited the activation of caspase-8 and the release of IL-1β in response to HK bacteria infection in human monocytes. Furthermore, we demonstrated that TAK1 activity mediated the expression of cFLIPs and was upstream and essential for the caspase-8 cleavage induced by HK bacteria in human monocytes. The functional specificity of cFLIPs and TAK1 revealed unique responses of human monocytes to a noninvasive pathogen, providing novel insights into an alternative regulatory pathway of NLRP3 inflammasome activation.PMID:37591930 | DOI:10.1038/s41423-023-01077-y
Source: Cellular and Molecular Immunology - Category: Molecular Biology Authors: Source Type: research