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Ticagrelor inhibits the NLRP3 inflammasome to protect against inflammatory disease independent of the P2Y12 signaling pathway

Cellular & Molecular Immunology volume 18, pages 1278–1289 (2021)Cite this article

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Abstract

Ticagrelor is the first reversibly binding oral P2Y12 receptor antagonist to inhibit platelet activation and has been approved by the Food and Drug Administration for the treatment of coronary artery disease. At present, the other pharmacological functions of ticagrelor remain poorly understood. The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a critical role in the innate immune system, but its excessive activation also contributes to the pathogenesis of complex diseases. In this study, we systematically examined the effects of ticagrelor on the NLRP3 inflammasome and found that ticagrelor inhibits NLRP3 inflammasome activation in macrophages independent of its classic inhibitory effect on the P2Y12 signaling pathway. Further mechanistic studies demonstrate that ticagrelor attenuates the oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC) by blocking chloride efflux, an effect achieved through the degradation of chloride intracellular channel proteins (CLICs) and blockade of the translocation of CLICs to the plasma membrane. Moreover, experiments on lipopolysaccharide-induced sepsis and alum-induced peritonitis in mice confirmed that ticagrelor mitigates the severity of systemic inflammation independent of P2Y12 receptor antagonism. Importantly, oral administration of ticagrelor rapidly and strongly inhibited NLRP3 inflammasome activation in peripheral blood mononuclear cells from patients with acute coronary syndrome. Overall, our study reveals a novel pharmacological function of ticagrelor in addition to its classic antiplatelet properties, which suggests that ticagrelor may serve as a potential therapeutic agent for use in NLRP3-associated diseases.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81773016, 21976155, and 31471297), Zhejiang Provincial Natural Science Foundation of China (No. LY18C060001), WeiJian Special Foundation (Zhejiang University School of Public Health), and Fundamental Research Funds for the Central Universities. The authors thank Professor Feng Shao (National Institute of Biological Sciences, Beijing, China) for providing iBMDMs. The authors thank Dr. Lain Charles Bruce (The University of Hong Kong) for his linguistic advice. The authors thank the Core Facilities at the Zhejiang University School of Medicine for providing technical support.

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  1. These authors contributed equally: Bo Huang, Yufeng Qian, Shujun Xie.

Authors and Affiliations

  1. Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Bo Huang, Shujun Xie, Hanwen Chen, Zhifeng Chen, Lihuan Zhang, Yihua Wu & Dajing Xia

  2. Department of Cardiology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Yufeng Qian & Xianhua Ye

  3. Translational Medicine Research Center, and Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Shujun Xie

  4. Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Jinming Xu

  5. Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China

    Hu Hu

  6. Department of Oncology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Shenglin Ma

  7. Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada

    Paul Héroux

  8. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China

    Di Wang

  9. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Han-Ming Shen

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Contributions

D.X., Y.W., B.H., Y.Q., S.X., X.Y., H.H., S.M., J.X., P.H., D.W., and H.-M.S. designed the study. B.H., Y.Q., S.X., H.C., Z.C., and L.Z. performed the experiments in this work. D.X., Y.W., B.H., and S.X. analyzed the data in this study. D.X., Y.W., and B.H. wrote the manuscript. All authors contributed to the discussion of the study and revision of the manuscript.

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Correspondence to Yihua Wu or Dajing Xia.

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Huang, B., Qian, Y., Xie, S. et al. Ticagrelor inhibits the NLRP3 inflammasome to protect against inflammatory disease independent of the P2Y12 signaling pathway. Cell Mol Immunol 18, 1278–1289 (2021). https://doi.org/10.1038/s41423-020-0444-5

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