Ticagrelor Inhibits The NLRP3 Inflammasome To Protect Against Inflammatory Disease

In response to pathogen-associated molecular patterns?PAMPs?or danger-associated molecular patterns?DAMPs?,NOD-,LRR-and pyrin domain-containing protein 3?NLRP3?recruits apoptosis-associated speck-like protein containing a CARD?ASC?and Pro-Caspase-1 to form multiprotein complexes termed inflammasome,mediating the maturation and release of Caspase-1 and IL-1?to protect against infection and damage.However,excessive activation of NLRP3 inflammasome contributes to complex diseases such as inflammatory disease and autoimmune disease.In this study,we found that ticagrelor,an oral P2Y purinoceptor 12(P2Y₁₂)receptor antagonist to inhibit platelet activation,functioned as a potent inhibitor of NLRP3 inflammasome in macrophages independent of its classical inhibitory effect on the P2Y₁₂ signaling pathway.Further mechanistic studies demonstrated that ticagrelor attenuated ASC specks formation via blocking chloride efflux,a process achieved though degradation of chloride intracellular channel proteins?CLICs?and blockage of translocation of CLICs to the membrane.Importantly,ticagrelor mitigated the severity of systematic inflammation in mouse models beyond P2Y₁₂receptor antagonism.Moreover,our study revealed that oral administration of ticagrelor rapidly and strongly inhibited NLRP3 inflammasome activation in peripheral blood mononuclear cells from patients with coronary artery disease.Therefore,ticagrelor might serve as a potential and potent inhibitor of the NLRP3 inflammasome to protect against harmful stimuli.