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

Cellular & Molecular Immunology
Bo HuangDajing Xia

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 severi...Continue Reading

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Citations

Sep 26, 2020·Frontiers in Cell and Developmental Biology·Benedikt KolbrinkStefan Krautwald
Jan 30, 2021·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Fengyang LiYunman Li
Apr 15, 2021·Cellular & Molecular Immunology·Seungwha PaikEun-Kyeong Jo
Jul 29, 2021·Cardiovascular Drugs and Therapy·Xiaohua LiXia Cao

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