当前位置: X-MOL 学术Biochem. J. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Immunothrombosis and the molecular control of tissue factor by pyroptosis: prospects for new anticoagulants
Biochemical Journal ( IF 4.4 ) Pub Date : 2022-03-31 , DOI: 10.1042/bcj20210522
Tristram A. J. Ryan 1 , Roger J. S. Preston 2 , Luke A. J. O'Neill 1
Affiliation  

The interplay between innate immunity and coagulation after infection or injury, termed immunothrombosis, is the primary cause of disseminated intravascular coagulation (DIC), a condition that occurs in sepsis. Thrombosis associated with DIC is the leading cause of death worldwide. Interest in immunothrombosis has grown because of COVID-19, the respiratory disease caused by SARS-CoV-2, which has been termed a syndrome of dysregulated immunothrombosis. As the relatively new field of immunothrombosis expands at a rapid pace, the focus of academic and pharmacological research has shifted from generating treatments targeted at the traditional ‘waterfall’ model of coagulation to therapies better directed towards immune components that drive coagulopathies. Immunothrombosis can be initiated in macrophages by cleavage of the non-canonical inflammasome which contains caspase-11. This leads to release of tissue factor (TF), a membrane glycoprotein receptor that forms a high-affinity complex with coagulation factor VII/VIIa to proteolytically activate factors IX to IXa and X to Xa, generating thrombin and leading to fibrin formation and platelet activation. The mechanism involves the post-translational activation of TF, termed decryption, and release of decrypted TF via caspase-11-mediated pyroptosis. During aberrant immunothrombosis, decryption of TF leads to thromboinflammation, sepsis, and DIC. Therefore, developing therapies to target pyroptosis have emerged as an attractive concept to counteract dysregulated immunothrombosis. In this review, we detail the three mechanisms of TF control: concurrent induction of TF, caspase-11, and NLRP3 (signal 1); TF decryption, which increases its procoagulant activity (signal 2); and accelerated release of TF into the intravascular space via pyroptosis (signal 3). In this way, decryption of TF is analogous to the two signals of NLRP3 inflammasome activation, whereby induction of pro-IL-1β and NLRP3 (signal 1) is followed by activation of NLRP3 (signal 2). We describe in detail TF decryption, which involves pathogen-induced alterations in the composition of the plasma membrane and modification of key cysteines on TF, particularly at the location of the critical, allosterically regulated disulfide bond of TF in its 219-residue extracellular domain. In addition, we speculate towards the importance of identifying new therapeutics to block immunothrombotic triggering of TF, which can involve inhibition of pyroptosis to limit TF release, or the direct targeting of TF decryption using cysteine-modifying therapeutics.

中文翻译:

免疫血栓形成和细胞焦亡对组织因子的分子控制:新型抗凝剂的前景

先天免疫与感染或损伤后的凝血(称为免疫血栓形成)之间的相互作用是播散性血管内凝血 (DIC) 的主要原因,DIC 是脓毒症中的一种疾病。与 DIC 相关的血栓形成是全球死亡的主要原因。由于 COVID-19(一种由 SARS-CoV-2 引起的呼吸道疾病,被称为免疫血栓形成失调综合征),人们对免疫血栓形成的兴趣日益浓厚。随着免疫血栓形成这一相对较新的领域快速发展,学术和药理学研究的重点已从针对传统“瀑布”凝血模型的治疗转移到更好地针对驱动凝血病的免疫成分的治疗。通过切割含有 caspase-11 的非经典炎性体,可以在巨噬细胞中引发免疫血栓形成。这导致组织因子 (TF) 的释放,这是一种膜糖蛋白受体,可与凝血因子 VII/VIIa 形成高亲和力复合物,以蛋白水解激活因子 IX 至 IXa 和 X 至 Xa,产生凝血酶并导致纤维蛋白形成和血小板活化. 该机制涉及 TF 的翻译后激活,称为解密,以及通过 caspase-11 介导的细胞焦亡释放解密的 TF。在异常免疫血栓形成期间,TF 的解密导致血栓炎症、败血症和 DIC。因此,开发针对细胞焦亡的疗法已成为对抗失调免疫血栓形成的有吸引力的概念。在这篇综述中,我们详细介绍了 TF 控制的三种机制:同时诱导 TF、caspase-11 和 NLRP3(信号 1);TF解密,增加其促凝血活性(信号2);并通过细胞焦亡加速 TF 释放到血管内空间(信号 3)。这样,TF 的解密类似于 NLRP3 炎性体激活的两个信号,即 pro-IL-1β 和 NLRP3(信号 1)的诱导之后是 NLRP3(信号 2)的激活。我们详细描述了 TF 解密,其中涉及病原体诱导的质膜组成改变和 TF 上关键半胱氨酸的修饰,特别是在 TF 在其 219 个残基细胞外结构域中关键的、变构调节的二硫键的位置。此外,我们推测确定新疗法以阻断免疫血栓触发 TF 的重要性,
更新日期:2022-03-31
down
wechat
bug