ASC regulates platelet activation and contributes to thrombus formation independent of NLRP3 inflammasome
ASC regulates platelet activation and contributes to thrombus formation independent of NLRP3 inflammasome
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DOI：
10.1016/j.bbrc.2020.07.063
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发表时间：
2020-10-15
影响因子：
3.1
通讯作者：
Takahashi, Masafumi
中科院分区：
文献类型：
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作者：
Watanabe, Sachiko;Usui-Kawanishi, Fumitake;Takahashi, Masafumi
背景：血小板是维持血管稳态和血栓形成的重要介质，也参与炎症的发生。NLRP 3炎性体是由NLRP 3、ASC和半胱天冬酶-1组成的胞质多蛋白复合物，并且调节IL-1 β介导的炎症。大脑中动脉和下腔静脉闭塞），我们发现与野生型（WT）和IL-1 β（-/-）小鼠相比，ASC缺陷（ASC（-/-））小鼠的血栓形成显著增强。ASC缺乏对凝血参数没有影响（即，凝血酶原时间[PT]和活化部分凝血活酶时间[APTT]）。来自WT小鼠的血小板表达ASC，但既不表达NLRP 3也不表达caspase-1。ASC缺乏显著增强了血小板中对GPVI激动剂（胶原相关肽[CRP]）的P-选择素和GPIIb/IIIa的表达，但对凝血酶没有影响。CRP诱导WT血小板中ASC斑点形成。ASC缺陷也增强了胞浆Ca 2+升高和ERK 1/2和Akt的磷酸化在platelet.Conclusion：我们的研究结果表明，ASC负调控GPVI信号在血小板和促进血栓形成，独立于NLRP 3 inflammasome和IL-1 β，并提供了新的见解炎症和血栓形成之间的联系。(C)2020爱思唯尔公司All rights reserved.
Background: Platelets are critical mediators of vascular homeostasis and thrombosis, and also contribute to the development of inflammation. NLRP3 inflammasome is a cytosolic multi-protein complex that consists of NLRP3, ASC and caspase-1, and regulates IL-1 beta-mediated inflammation.Method and Results: Using two mouse models of thrombosis (i.e., occlusion of the middle cerebral artery and inferior vena cava), we found that thrombus formation was significantly enhanced in ASC-deficient (ASC(-/-)) mice, compared to that in wild-type (WT) and IL-1 beta(-/-) mice. ASC deficiency had no effects on blood coagulation parameters (i.e., prothrombin time [PT] and activated partial thromboplastin time [APTT]). Platelets from WT mice express ASC, but neither NLRP3 nor caspase-1. ASC deficiency significantly enhanced the expression of P-selectin and GPIIb/IIIa in response to a GPVI agonist (collagen-related peptide [CRP]), but not to thrombin, in platelets. CRP induced ASC speck formation in WT platelets. ASC deficiency also enhanced cytosolic Ca2+ elevation and phosphorylation of ERK1/2 and Akt in platelets.Conclusion: Our results demonstrate that ASC negatively regulates GPVI signaling in platelets and enhances thrombus formation, independent of NLRP3 inflammasome and IL-1 beta, and provide novel insights into the link between inflammation and thrombosis. (C) 2020 Elsevier Inc. All rights reserved.