Activation of NLRP3 inflammasome complex potentiates venous thrombosis in response to hypoxia
Activation of NLRP3 inflammasome complex potentiates venous thrombosis in response to hypoxia
复制标题
NLRP3炎性体复合物的激活增强了对缺氧反应的静脉血栓形成
DOI：
10.1073/pnas.1620458114
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发表时间：
2017-05-02
影响因子：
11.1
通讯作者：
Ashraf, Mohammad Zahid
中科院分区：
文献类型：
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作者：
Gupta, Neha;Sahu, Anita;Ashraf, Mohammad Zahid
由止血改变引起的静脉血栓栓塞 (VTE) 仍然是所有心血管疾病中第三大常见的死亡原因。除了已确定的遗传和后天风险因素外，低氧环境也使其他健康的个体容易发生静脉血栓栓塞。尽管疾病病因似乎涉及止血途径的扰动，但早期反应期间的关键分子决定因素仍然难以捉摸。使用已建立的静脉血栓形成模型，我们在此表明，全身性缺氧会加速血栓栓塞事件，其功能受到核苷酸结合域、富含亮氨酸家族、含有吡啶域的 3 (NLRP3) 炎性体复合物的激活和 IL-1 β 分泌增加的功能刺激。有趣的是，我们还表明，在这些条件下，NLRP3 的表达是由缺氧诱导因子 1-α (HIF-1 α) 介导的。 Caspase-1 的药理抑制、体内 NLRP3 或 HIF-1 α（IL-1 β 中和抗体除外）的敲低可减弱缺氧条件下炎症小体的激活并减少血栓形成。我们通过研究高原诱发的静脉血栓形成患者中该通路的调节来扩展这些临床前发现的意义。我们的结果表明，在临床确诊的静脉血栓形成个体中，NLRP3、caspase-1 和 IL-1 beta 的表达明显增加。因此，我们提出，由 HIF 诱导的 NLRP3 炎性体复合物精心策划的静脉环境中的早期促炎状态是缺氧条件下急性血栓事件的关键决定因素。
Venous thromboembolism (VTE), caused by altered hemostasis, remains the third most common cause of mortality among all cardiovascular conditions. In addition to established genetic and acquired risk factors, low-oxygen environments also predispose otherwise healthy individuals to VTE. Although disease etiology appears to entail perturbation of hemostasis pathways, the key molecular determinants during immediate early response remain elusive. Using an established model of venous thrombosis, we here show that systemic hypoxia accelerates thromboembolic events, functionally stimulated by the activation of nucleotide binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome complex and increased IL-1 beta secretion. Interestingly, we also show that the expression of NLRP3 is mediated by hypoxia-inducible factor 1-alpha (HIF-1 alpha) during these conditions. The pharmacological inhibition of caspase-1, in vivo knockdown of NLRP3, or HIF-1 alpha other than IL-1 beta-neutralizing antibodies attenuated inflammasome activation and curtailed thrombosis under hypoxic conditions. We extend the significance of these preclinical findings by studying modulation of this pathway in patients with altitude-induced venous thrombosis. Our results demonstrate distinctive, increased expression of NLRP3, caspase-1, and IL-1 beta in individuals with clinically established venous thrombosis. We therefore propose that an early proinflammatory state in the venous milieu, orchestrated by the HIF-induced NLRP3 inflammasome complex, is a key determinant of acute thrombotic events during hypoxic conditions.