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USP19 suppresses inflammation and promotes M2-like macrophage polarization by manipulating NLRP3 function via autophagy

Cellular & Molecular Immunology volume 18, pages 2431–2442 (2021)Cite this article

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Abstract

Macrophage polarization to proinflammatory M1-like or anti-inflammatory M2-like cells is critical to mount a host defense or repair tissue. The exact molecular mechanisms controlling this process are still elusive. Here, we report that ubiquitin-specific protease 19 (USP19) acts as an anti-inflammatory switch that inhibits inflammatory responses and promotes M2-like macrophage polarization. USP19 inhibited NLRP3 inflammasome activation by increasing autophagy flux and decreasing the generation of mitochondrial reactive oxygen species. In addition, USP19 inhibited the proteasomal degradation of inflammasome-independent NLRP3 by cleaving its polyubiquitin chains. USP19-stabilized NLRP3 promoted M2-like macrophage polarization by direct association with interferon regulatory factor 4, thereby preventing its p62-mediated selective autophagic degradation. Consistent with these observations, compared to wild-type mice, Usp19−/− mice had decreased M2-like macrophage polarization and increased interleukin-1β secretion, in response to alum and chitin injections. Thus, we have uncovered an unexpected mechanism by which USP19 switches the proinflammatory function of NLRP3 into an anti-inflammatory function, and suggest that USP19 is a potential therapeutic target for inflammatory interventions.

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Acknowledgements

This work was supported by the National Key Research and Development Project (2020YFA0908700) and the National Natural Science Foundation of China (31870862 and 31700760).

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  1. These authors contributed equally: Tao Liu, Liqiu Wang, Puping Liang

Authors and Affiliations

  1. MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, 510275, Guangzhou, Guangdong, People’s Republic of China

    Tao Liu, Liqiu Wang, Puping Liang, Yukun Liu, Jing Cai, Yuanchu She, Junjiu Huang & Jun Cui

  2. Department of Experimental Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University, 510275, Guangzhou, People’s Republic of China

    Xiaojuan Wang, Dan Wang, Xiaojun Xia & Jun Cui

  3. Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Stomatological Hospital, Sun Yat-Sen University, 510060, Guangzhou, Guangdong, People’s Republic of China

    Zhi Wang

  4. Organ Transplant Center, The First Affiliated Hospital, Sun Yat-Sen University, 510080, Guangzhou, Guangdong, People’s Republic of China

    Zhiyong Guo

  5. Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

    Samuel Bates

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Contributions

T.L., L.W., and P.L. performed the experiments and analyzed the results. X.W., Y.L., J.C., Y.S., D.W., Z.W., Z.G., and X.X. provided technical help. J.C. and J.H. initiated and designed the project, and directed the research. T.L., S.B., and J.C. wrote the manuscript.

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Correspondence to Junjiu Huang or Jun Cui.

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Liu, T., Wang, L., Liang, P. et al. USP19 suppresses inflammation and promotes M2-like macrophage polarization by manipulating NLRP3 function via autophagy. Cell Mol Immunol 18, 2431–2442 (2021). https://doi.org/10.1038/s41423-020-00567-7

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