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The inhibitor effect of RKIP on inflammasome activation and inflammasome-dependent diseases

Cellular & Molecular Immunology volume 18, pages 992–1004 (2021)Cite this article

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Abstract

Aberrant inflammasome activation contributes to the pathogenesis of various human diseases, including atherosclerosis, gout, and metabolic disorders. Elucidation of the underlying mechanism involved in the negative regulation of the inflammasome is important for developing new therapeutic targets for these diseases. Here, we showed that Raf kinase inhibitor protein (RKIP) negatively regulates the activation of the NLRP1, NLRP3, and NLRC4 inflammasomes. RKIP deficiency enhanced caspase-1 activation and IL-1β secretion via NLRP1, NLRP3, and NLRC4 inflammasome activation in primary macrophages. The overexpression of RKIP in THP-1 cells inhibited NLRP1, NLRP3, and NLRC4 inflammasome activation. RKIP-deficient mice showed increased sensitivity to Alum-induced peritonitis and Salmonella typhimurium-induced inflammation, indicating that RKIP inhibits NLRP3 and NLRC4 inflammasome activation in vivo. Mechanistically, RKIP directly binds to apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and competes with NLRP1, NLRP3, or NLRC4 to interact with ASC, thus interrupting inflammasome assembly and activation. The depletion of RKIP aggravated inflammasome-related diseases such as monosodium urate (MSU)-induced gouty arthritis and high-fat diet (HFD)-induced metabolic disorders. Furthermore, the expression of RKIP was substantially downregulated in patients with gouty arthritis or type 2 diabetes (T2D) compared to healthy controls. Collectively, our findings suggest that RKIP negatively regulates NLRP1, NLRP3, and NLRC4 inflammasome activation and is a potential therapeutic target for the treatment of inflammasome-related diseases.

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Acknowledgements

We thank Professor John Sedivy for the Rkip-knockout mice, Professor Kam C. Yeung for the Rkipf/f mice and Dr Rongbin Zhou for the plasmids. This work was supported by the National Natural Science Foundation of China (81972733) and the Natural Science Foundation of Zhejiang Province (LY19H160048).

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  1. These authors contributed equally: Qiang Qin, Huan Liu

Authors and Affiliations

  1. Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, PR China

    Qiang Qin, Hong Yu & Xiaojian Wang

  2. Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China

    Qiang Qin, Huan Liu, Jia’nan Shou & Xiaojian Wang

  3. Department of Clinical Laboratory Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, PR China

    Yu Jiang

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X.W. and H.Y. designed the research; Q.Q., H.L., J.S., and Y.J. performed the research; X.W. and Q.Q. analyzed the data and wrote the paper.

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Correspondence to Hong Yu or Xiaojian Wang.

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Qin, Q., Liu, H., Shou, J. et al. The inhibitor effect of RKIP on inflammasome activation and inflammasome-dependent diseases. Cell Mol Immunol 18, 992–1004 (2021). https://doi.org/10.1038/s41423-020-00525-3

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