Ticagrelor inhibits the NLRP3 inflammasome to protect against inflammatory disease independent of the P2Y12signaling pathway
Ticagrelor inhibits the NLRP3 inflammasome to protect against inflammatory disease independent of the P2Y12signaling pathway
复制标题
替格瑞洛抑制 NLRP3 炎症小体以预防独立于 P2Y12 信号通路的炎症性疾病
DOI：
10.1038/s41423-020-0444-5
复制
发表时间：
2020-06-10
影响因子：
24.1
通讯作者：
Xia, Dajing
中科院分区：
文献类型：
--
作者：
Huang, Bo;Qian, Yufeng;Xia, Dajing
替卡格雷是第一种可逆结合的口服P2Y12受体拮抗剂，可抑制血小板激活，并已被美国食品和药物管理局批准用于治疗冠心病。目前，替卡格雷的其他药理作用仍知之甚少。NLRP3在天然免疫系统中起重要作用，但其过度激活也参与了复杂疾病的发病。在这项研究中，我们系统地检测了替卡格雷对NLRP3炎症体的影响，发现替卡格雷抑制巨噬细胞中NLRP3炎症体的激活，而不是经典的对P2Y12信号通路的抑制作用。进一步的机制研究表明，替卡格雷通过抑制氯离子外流来减弱含有卡片的凋亡相关斑点样蛋白(ASC)的寡聚化，这种作用是通过降解氯离子细胞内通道蛋白(CLICS)和阻断CLICS向质膜的移位来实现的。此外，对脂多糖诱导的小鼠脓毒症和明胶诱导的腹膜炎的实验证实，替卡格雷减轻全身炎症的严重程度不依赖于P2Y12受体拮抗作用。重要的是，口服替卡格雷能迅速而强烈地抑制急性冠脉综合征患者外周血单个核细胞中NLRP3炎性小体的激活。总体而言，我们的研究揭示了替卡格雷除了其经典的抗血小板特性外，还有一种新的药理功能，这表明替卡格雷可能作为一种潜在的治疗药物用于NLRP3相关疾病。
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.