Abstract
Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases. However, the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unknown. In this study, we demonstrated that S-nitrosoglutathione reductase (GSNOR) deficiency in macrophages leads to significant increases in the Nlrp3 and Il-1β expression levels and interleukin-1β (IL-1β) secretion in response to NLRP3 inflammasome stimulation. Furthermore, in vivo experiments utilizing Gsnor−/− mice revealed increased disease severity in both lipopolysaccharide (LPS)-induced septic shock and dextran sodium sulfate (DSS)-induced colitis models. Additionally, we showed that both LPS-induced septic shock and DSS-induced colitis were ameliorated in Gsnor−/− Nlrp3−/− double-knockout (DKO) mice. Mechanistically, GSNOR deficiency increases the S-nitrosation of mitogen-activated protein kinase 14 (MAPK14) at the Cys211 residue and augments MAPK14 kinase activity, thereby promoting Nlrp3 and Il-1β transcription and stimulating NLRP3 inflammasome activity. Our findings suggested that GSNOR is a regulator of the NLRP3 inflammasome and that reducing the level of S-nitrosylated MAPK14 may constitute an effective strategy for alleviating diseases associated with NLRP3-mediated inflammation.
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Acknowledgements
The authors thank Prof. Rongbin Zhou for sharing the Nlrp3−/− mice. We are grateful to Dr. Ian Logan for the helpful comments and language editing of this manuscript. This study was supported by Yunnan Fundamental Research Project (202305AH340006), the National Natural Science Foundation of China (32201018), the Basic Research Program and Key Project of Yunnan Province (202301AW070013 and 202003AD150009), and the Youth Innovation Promotion Association (2023403).
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Yong-Gang Yao and Qianjin Liu conceived and designed the experiments. Qianjin Liu, Lijin Jiao, Zhiyu Ma, Jinsong Yu, Ling-Yan Su, Wei-Yin Zou and Lu-Xiu Yang performed the cellular and mouse experiments. Mao-Sen Ye performed the RNA-seq data analysis. Chang Chen provided mouse lines and provided constructive suggestions. Yong-Gang Yao and Qianjin Liu wrote the manuscript. All authors reviewed the content and approved the final version for publication.
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Liu, Q., Jiao, L., Ye, MS. et al. GSNOR negatively regulates the NLRP3 inflammasome via S-nitrosation of MAPK14. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01155-9
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DOI: https://doi.org/10.1038/s41423-024-01155-9
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