A critical role for plasminogen in inflammation

Abstract

Plasminogen and its active form, plasmin, have diverse functions related to the inflammatory response in mammals. Due to these roles in inflammation, plasminogen has been implicated in the progression of a wide range of diseases with an inflammatory component. In this review, we discuss the functions of plasminogen in inflammatory regulation and how this system plays a role in the pathogenesis of diseases spanning organ systems throughout the body.

Figure 1.

Overview of the plasminogen activator system. PAI-1, PAI-2, and nexin serve as inhibitors for the plasminogen activators tPA and uPA. Plasminogen is activated by tPA or uPA to form plasmin, which can then be inactivated by α₂-antiplasmin. The major substrate for plasmin is fibrin, which is formed via the coagulation cascade following cleavage of fibrinogen by thrombin. Plasmin degrades fibrin into fibrin degradation products.

Figure 2.

Overview of the ways plasminogen (PLG) contributes to inflammation. (1) The major substrate for plasmin is fibrin. Following fibrin clot formation through the coagulation cascade, plasminogen participates in fibrinolysis by binding to the fibrin clot along with tPA. It becomes activated to form plasmin, which will then degrade the clot, resulting in the formation of fibrin degradation products. (2) Plasminogen interacts with several proteins of the complement cascade including C3, C3b, C5, and C4BP, which may aid in the modulation of the complement inflammatory response. (3) Cell surface–bound plasmin aids in ECM degradation by activating MMPs that can degrade collagen and other proteins in the blood vessel wall. (4) Plasmin binds to cells via plasminogen receptors (PLG-Rs), which can lead to migration of leukocytes, neutrophils, monocytes, and macrophages. Note that this function is often fibrin dependent; thus fibrinolysis is an important part of plasmin-mediated cell migration. (5) Plasminogen participates in wound healing by clearing fibrin and neutrophils once they are no longer needed at the injured site. Plasminogen also aids in polarization of M1 (proinflammatory) macrophages into M2 (anti-inflammatory) macrophages during this phase.