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Innate immune signaling and immunothrombosis: New insights and therapeutic opportunities
European Journal of Immunology ( IF 4.5 ) Pub Date : 2022-05-15 , DOI: 10.1002/eji.202149410
Tristram A J Ryan 1 , Luke A J O'Neill 1
Affiliation  

Activation of the coagulation cascade is a critical, evolutionarily conserved mechanism that maintains hemostasis by rapidly forming blood clots in response to blood-borne infections and damaged blood vessels. Coagulation is a key component of innate immunity since it prevents bacterial dissemination and can provoke inflammation. The term immunothrombosis describes the process by which the innate immune response drives aberrant coagulation, which can result in a lethal condition termed disseminated intravascular coagulation, often seen in sepsis. In this review, we describe the recently uncovered molecular mechanisms underlying inflammasome- and STING-driven immunothrombosis induced by bacterial and viral infections, culminating in tissue factor (TF) activation and release. Current anticoagulant therapeutics, while effective, are associated with a life-threatening bleeding risk, requiring the urgent development of new treatments. Targeting immunothrombosis may provide a safer option. Thus, we highlight preclinical tools which target TF and/or block canonical (NLRP3) or noncanonical (caspase-11) inflammasome activation as well as STING-driven TF release and discuss clinically approved drugs which block key immunothrombotic processes and, therefore, may be redeployed as safer anticoagulants.

中文翻译:


先天免疫信号传导和免疫血栓形成:新见解和治疗机会



凝血级联的激活是一种重要的、进化上保守的机制,它通过快速形成血块来响应血源性感染和受损血管来维持止血。凝血是先天免疫的关键组成部分,因为它可以防止细菌传播并引发炎症。免疫血栓形成一词描述了先天免疫反应驱动异常凝血的过程,这可能导致称为弥散性血管内凝血的致命病症,常见于脓毒症。在这篇综述中,我们描述了最近发现的由细菌和病毒感染诱导的炎性体和 STING 驱动的免疫血栓形成的分子机制,最终导致组织因子 (TF) 的激活和释放。目前的抗凝治疗虽然有效,但与危及生命的出血风险相关,需要紧急开发新的治疗方法。针对免疫血栓形成可能提供更安全的选择。因此,我们重点介绍针对 TF 和/或阻断典型 (NLRP3) 或非典型 (caspase-11) 炎症小体激活以及 STING 驱动的 TF 释放的临床前工具,并讨论临床批准的阻断关键免疫血栓形成过程的药物,因此可能是重新部署为更安全的抗凝剂。
更新日期:2022-05-15
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