cFLIPS regulates alternative NLRP3 inflammasome activation in human monocytes

  • Cell Mol Immunol. 2023 Aug 17. doi: 10.1038/s41423-023-01077-y.
Yuhui Gao  #  1  2 ,  Shi Yu  #  2  3 ,  Mengdan Chen  2 ,  Xun Wang  4 ,  Lei Pan  2  5 ,  Bin Wei  6 ,  Guangxun Meng  7  8  9
Affiliations
  • 1. School of Life Sciences, Shanghai University, Shanghai, 200444, China.
  • 2. The Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology & Immunology, University of Chinese Academy of Sciences, Shanghai, 200031, China.
  • 3. Department of Basic Research, Guangzhou Laboratory, Guangzhou International Bio-Island, Guangzhou, 510005, Guangdong, China.
  • 4. Shanghai Blood Center, Shanghai, 200051, China.
  • 5. Pasteurien College, Soochow University, Suzhou, 215006, Jiangsu, China.
  • 6. School of Life Sciences, Shanghai University, Shanghai, 200444, China. [email protected].
  • 7. The Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology & Immunology, University of Chinese Academy of Sciences, Shanghai, 200031, China. [email protected].
  • 8. Pasteurien College, Soochow University, Suzhou, 215006, Jiangsu, China. [email protected].
  • 9. Nanjing Advanced Academy of Life and Health, Nanjing, 211135, Jiangsu, China. [email protected].
  • # Contributed equally.
PMID: 37591930 DOI: 10.1038/s41423-023-01077-y
Abstract

The 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.

Keywords
NLRP3 inflammasome; cFLIPS; gram-negative bacteria; human monocyte.
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