2. Academic Validation
  3. TRAF6-TAK1-IKKβ pathway mediates TLR2 agonists activating "one-step" NLRP3 inflammasome in human monocytes

TRAF6-TAK1-IKKβ pathway mediates TLR2 agonists activating "one-step" NLRP3 inflammasome in human monocytes

  • Cytokine. 2023 Jul 20;169:156302. doi: 10.1016/j.cyto.2023.156302.
Mengdan Chen 1,  Shi Yu 1,  Yuhui Gao 2,  Jiaxun Li 1,  Xun Wang 3,  Bin Wei 4,  Guangxun Meng 5
Affiliations

Affiliations

  • 1 The Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology & Immunology, University of Chinese Academy of Sciences, Shanghai 200031, 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; School of Life Sciences, Shanghai University, Shanghai 200444, China.
  • 3 Shanghai Blood Center, Shanghai 200051, China.
  • 4 School of Life Sciences, Shanghai University, Shanghai 200444, China.
  • 5 The Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology & Immunology, University of Chinese Academy of Sciences, Shanghai 200031, China; Pasteurien College, Soochow University, Suzhou, Jiangsu 215006, China; Nanjing Advanced Academy of Life and Health, Nanjing, Jiangsu 211135, China. Electronic address: gxmeng@ips.ac.cn.
PMID: 37480791 DOI: 10.1016/j.cyto.2023.156302
Abstract

Gram-positive Bacterial infection causes high morbidity and mortality worldwide, while the underlying mechanism for host sensing Bacterial components and initiating immune responses remains elusive. The NLRP3 inflammasome is a cytosolic multi-protein complex sensing a broad spectrum of endogenous danger signals and environmental irritants. In contrast to canonical NLRP3 inflammasome activation that needs both priming and activation signals, Lipopolysaccharide (LPS) from gram-negative bacteria activates the "one-step" NLRP3 inflammasome in human monocytes, which relies on the TLR4-TRIF-Caspase-8 signaling. Here, we show that in human monocytes, TLR2 agonists such as heat-killed gram-positive bacteria, peptidoglycan (PGN) or synthetic Bacterial lipoprotein analog Pam3CysSerLys4 (Pam3CSK4) are able to induce the "one-step" NLRP3 inflammasome activation. Using genetic targeting and pharmacological inhibition approaches, it was found that TLR2 propagates signal through TRAF6, TAK1 and IKKβ, ultimately activated NLRP3 independent of RelA. In addition, IKKβ interacts with NLRP3 directly and affects NLRP3 inflammasome activation. These results reveal the signaling cascade downstream of TLR2 upon sensing gram-positive Bacterial infection and activating the "one-step" NLRP3 inflammasome in human monocytes, which provides clue for controlling gram-positive Bacterial infection-related inflammation.

Keywords

Monocytes; NLRP3 inflammasome; TLR2; TRAF6-TAK1-IKKβ pathway.

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  • HY-13019
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