The Coagulation and Immune Systems Are Directly Linked through the Activation of Interleukin-1α by Thrombin
The Coagulation and Immune Systems Are Directly Linked through the Activation of Interleukin-1α by Thrombin
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DOI：
10.1016/j.immuni.2019.03.003
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发表时间：
2019-04-16
期刊：
影响因子：
32.4
通讯作者：
Clarke, Murray C. H.
中科院分区：
文献类型：
--
作者：
Burzynski, Laura C.;Humphry, Melanie;Clarke, Murray C. H.
古老的生物体具有结合的凝血和免疫系统，尽管炎症和止血之间的联系存在于哺乳动物中，但它们是间接的，并且作用较慢。在这里，我们研究了哺乳动物的免疫和凝血系统之间的直接联系，通过检查潜在的凝血酶蛋白酶的共识网站的细胞因子前蛋白。我们发现，白细胞介素（IL）-1 α是直接激活凝血酶。凝血酶在不同物种中完全保守的位点切割pro-IL-1 α，表明其功能重要性。巨噬细胞和活化的血小板上的表面IL-1 α前体被凝血酶切割和活化，而组织因子，一种有效的凝血酶活化剂，与表皮中的IL-1 α前体共定位。携带IL-1 α凝血酶裂解位点突变（R114 Q）的小鼠在急性血小板丢失后表现出有效伤口愈合和快速血小板生成的缺陷。在脓毒症期间，在人体中检测到了凝血酶切割的IL-1 α，这表明该途径与正常生理机能以及炎症和血栓性疾病的发病机制相关。
Ancient organisms have a combined coagulation and immune system, and although links between inflammation and hemostasis exist in mammals, they are indirect and slower to act. Here we investigated direct links between mammalian immune and coagulation systems by examining cytokine proproteins for potential thrombin protease consensus sites. We found that interleukin (IL)-1 alpha is directly activated by thrombin. Thrombin cleaved pro-IL-1 alpha at a site perfectly conserved across disparate species, indicating functional importance. Surface pro-IL-1 alpha on macrophages and activated platelets was cleaved and activated by thrombin, while tissue factor, a potent thrombin activator, colocalized with pro-IL1 alpha in the epidermis. Mice bearing a mutation in the IL-1 alpha thrombin cleavage site (R114Q) exhibited defects in efficient wound healing and rapid thrombopoiesis after acute platelet loss. Thrombin-cleaved IL-1 alpha was detected in humans during sepsis, pointing to the relevance of this pathway for normal physiology and the pathogenesis of inflammatory and thrombotic diseases.