Department of Immunological Diagnosis, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan.
An-Najah Center for Cancer and Stem Cell Research, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine.
Cell Signal. 2020 Nov;75:109761. doi: 10.1016/j.cellsig.2020.109761. Epub 2020 Aug 28.
A fine-tuned activation and deactivation of proteases and their inhibitors are involved in the execution of the inflammatory response. The zymogen/proenzyme plasminogen is converted to the serine protease plasmin, a key fibrinolytic factor by plasminogen activators including tissue-type plasminogen activator (tPA). Plasmin is part of an intricate protease network controlling proteins of initial hemostasis/coagulation, fibrinolytic and complement system. Activation of these protease cascades is required to mount a proper inflammatory response. Although best known for its ability to dissolve clots and cleave fibrin, recent studies point to the importance of fibrin-independent functions of plasmin during acute inflammation and inflammation resolution. In this review, we provide an up-to-date overview of the current knowledge of the enzymatic and cytokine-like effects of tPA and describe the role of tPA and plasminogen receptors in the regulation of the inflammatory response with emphasis on the cytokine storm syndrome such as observed during coronavirus disease 2019 or macrophage activation syndrome. We discuss tPA as a modulator of Toll like receptor signaling, plasmin as an activator of NFkB signaling, and summarize recent studies on the role of plasminogen receptors as controllers of the macrophage conversion into the M2 type and as mediators of efferocytosis during inflammation resolution.
蛋白酶及其抑制剂的精细激活和失活参与了炎症反应的执行。酶原/酶原纤溶酶原通过包括组织型纤溶酶原激活物 (tPA) 在内的纤溶酶原激活物转化为丝氨酸蛋白酶纤溶酶，这是一种关键的纤维蛋白溶解因子。纤溶酶是控制初始止血/凝血、纤维蛋白溶解和补体系统蛋白的复杂蛋白酶网络的一部分。这些蛋白酶级联的激活对于引发适当的炎症反应是必需的。尽管纤溶酶以溶解血栓和切割纤维蛋白的能力而闻名，但最近的研究表明，在急性炎症和炎症消退过程中，纤溶酶具有纤维蛋白非依赖性功能。在这篇综述中，我们提供了关于 tPA 的酶和细胞因子样作用的最新知识概述，并描述了 tPA 和纤溶酶原受体在调节炎症反应中的作用，重点介绍了细胞因子风暴综合征，如在 2019 年冠状病毒病或巨噬细胞活化综合征中观察到的。我们讨论了 tPA 作为 Toll 样受体信号的调节剂，纤溶酶作为 NFkB 信号的激活剂，并总结了最近关于纤溶酶原受体作为控制巨噬细胞向 M2 型转化以及在炎症消退过程中作为吞噬作用介质的作用的研究。
