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Priming of NLRP3 inflammasome activation by Msn kinase MINK1 in macrophages

Cellular & Molecular Immunology volume 18, pages 2372–2382 (2021)Cite this article

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Abstract

The nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome is essential in inflammation and inflammatory disorders. Phosphorylation at various sites on NLRP3 differentially regulates inflammasome activation. The Ser725 phosphorylation site on NLRP3 is depicted in multiple inflammasome activation scenarios, but the importance and regulation of this site has not been clarified. The present study revealed that the phosphorylation of Ser725 was an essential step for the priming of the NLRP3 inflammasome in macrophages. We also showed that Ser725 was directly phosphorylated by misshapen (Msn)/NIK-related kinase 1 (MINK1), depending on the direct interaction between MINK1 and the NLRP3 LRR domain. MINK1 deficiency reduced NLRP3 activation and suppressed inflammatory responses in mouse models of acute sepsis and peritonitis. Reactive oxygen species (ROS) upregulated the kinase activity of MINK1 and subsequently promoted inflammasome priming via NLRP3 Ser725 phosphorylation. Eliminating ROS suppressed NLRP3 activation and reduced sepsis and peritonitis symptoms in a MINK1-dependent manner. Altogether, our study reveals a direct regulation of the NLRP3 inflammasome by Msn family kinase MINK1 and suggests that modulation of MINK1 activity is a potential intervention strategy for inflammasome-related diseases.

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Acknowledgements

The authors thank Xinhui Song, Chun Guo, Jiajia Wang, and Yingying Huang from the core facilities (Zhejiang University School of Medicine) for technical assistance in histology and FACS analysis. The authors are grateful to Prof. Fan Yang and Wenxuan Zhen for human NLRP3-NEK7 symmetric docking. The authors thank the Key Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province for their support. This work was supported by grants from the National Natural Science Foundation of China (31930038, 31770954, and 31530019 to L.L.).

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  1. These authors contributed equally: Kaixiang Zhu, Xuexiao Jin.

Authors and Affiliations

  1. Institute of Immunology and Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, P. R. China

    Kaixiang Zhu, Xuexiao Jin & Linrong Lu

  2. Zhejiang University–University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, 314400, P. R. China

    Kaixiang Zhu, Richard D. Sloan & Linrong Lu

  3. Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, 310058, P. R. China

    Kaixiang Zhu & Xuai Lin

  4. Department of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, P. R. China

    Zhexu Chi, Sheng Chen & Di Wang

  5. Department of Colorectal Surgery, The Second Affiliated Hospital, Hangzhou, 310058, P. R. China

    Sheng Chen

  6. Medical College, Lishui University, Lishui, 323000, P. R. China

    Songquan Wu

  7. Infection Medicine, School of Biomedical Sciences, The University of Edinburgh, Edinburgh, EH16 4SB, Scotland, UK

    Richard D. Sloan

  8. Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, 310058, P. R. China

    Dante Neculai

  9. Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, 310058, P. R. China

    Hu Hu

  10. Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, P. R. China

    Linrong Lu

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  1. Kaixiang Zhu
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Contributions

K.Z., X.J., D.W., X.L. and L.L. designed the research. K.Z., X.J., Z.C., S.C. and S.W. performed the research. K.Z., X.J. and L.L. analyzed the data. K.Z., X.J. and L.L. wrote the paper. R.D.S., H.H. and D.N. edited the paper.

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Correspondence to Linrong Lu.

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Zhu, K., Jin, X., Chi, Z. et al. Priming of NLRP3 inflammasome activation by Msn kinase MINK1 in macrophages. Cell Mol Immunol 18, 2372–2382 (2021). https://doi.org/10.1038/s41423-021-00761-1

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