Plasmin as a proinflammatory cell activator

Abstract

The serine protease plasmin generated from its zymogen plasminogen is best known for its function as a key enzyme of the fibrinolytic cascade. However, beyond fibrinolysis, plasmin has a number of crucial functions in a variety of processes, including inflammation. Various cells can bind plasminogen and plasmin via plasminogen-binding sites exposing a C-terminal lysine. Plasmin, generated as a result of plasminogen activation at the cell surface, is protected from its physiological inhibitors. Apart from its ability to facilitate cell migration in tissues, plasmin is capable of triggering signaling, which depends on cellular binding via its lysine-binding sites and its proteolytic activity. Plasmin-induced signaling affects various functions of monocytes, macrophages, DCs, and others, with the list of affected cells still growing. In vitro and in vivo studies have demonstrated the ability of plasmin to stimulate the production of cytokines, ROS, and other mediators, thereby contributing to inflammation. Plasmin-induced chemotaxis of monocytes and DCs indicates that it is also a potent chemoattractant for immune cells. Therefore, excessive activation of plasmin in chronic inflammatory or autoimmune diseases might exacerbate the activation of inflammatory cells and the pathogenesis of the disease. This review focuses on the available evidence for physiological and pathophysiological roles the serine protease plasmin in inflammatory processes.

Plasmin Induces In Vivo Monocyte Recruitment through Protease-Activated Receptor-1–, MEK/ERK-, and CCR2-Mediated Signaling

“…We showed in the present study that Plg induced cell migration to a similar extent as did Pla. It has been stated that Plg is quickly converted to Pla by urokinase-type Plg activator or tissue-type Plg activator, and protease activity of Pla is essential on Plg-induced migration (4,11). Thus, it is likely that urokinase-type Plg activator generated in the pleural milieu after the injection may be activating the exogenously administered Plg and promoting cell migration.…”

“…T he plasminogen (Plg)/plasmin (Pla) proteolytic system is activated by the conversion of the zymogen Plg into the serine protease Pla mainly through the proteolytic activity of urokinase-type Plg activator and tissue-type Plg activator (1)(2)(3)(4). The primary function in vivo of Pla is to degrade fibrin clots and regulate vascular patency (1,2).…”

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

“…In addition, rt-PA has been shown to increase tissue injury and enhance neutrophil tissue infiltration following ischaemiareperfusion injury to the brain 60 , lung 61 and kidneys 62 . The known proinflammatory function of recombinant t-PA has been partly attributed to its direct activating effects on the endothelium and inflammatory cells, as well as through the generation of fibrin degradation products 63 and plasmin 64 . In addition to these well-known proinflammatory effects, the studies presented here define an additional mechanism by which rt-PA may enhance thromboinflammatory responses by undermining the physical barrier function of fibrin on leukocyte migration.…”

The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

“…For example, plasmin has been shown to promote the activation of inflammatory cells, including neutrophils (Syrovets et al, 2012), which contribute to liver necrosis induced by cholestasis (Gujral et al, 2003). Of interest, at a 2-week time point where it significantly reduced liver injury, TA treatment did not affect hepatic expression of mRNAs encoding numerous chemokines, including MCP-1, MIP-2, and KC (data not shown).…”