Ticagrelor inhibits the NLRP3 inflammasome to protect against inflammatory disease independent of the P2Y 12 signaling pathway.

Autor: Huang B; Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China., Qian Y; Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China., Xie S; Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.; 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., Ye X; Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China., Chen H; Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China., Chen Z; Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China., Zhang L; Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China., Xu J; Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China., Hu H; Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China., Ma S; Department of Oncology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China., Héroux P; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada., Wang D; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China., Shen HM; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Wu Y; Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. georgewu@zju.edu.cn., Xia D; Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. dxia@zju.edu.cn.
Jazyk: angličtina
Zdroj: Cellular & molecular immunology [Cell Mol Immunol] 2021 May; Vol. 18 (5), pp. 1278-1289. Date of Electronic Publication: 2020 Jun 10.
DOI: 10.1038/s41423-020-0444-5
Abstrakt: Ticagrelor is the first reversibly binding oral P2Y 12 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 P2Y 12 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 P2Y 12 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.
Databáze: MEDLINE
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