Abstract

The fibrinolytic system provides an essential means to remove fibrin deposits and blood clots. The actual protease responsible for this is plasmin, formed from its precursor, plasminogen. Fibrin is heralded as it most renowned substrate but for many years plasmin has been known to cleave many other substrates, and to also activate other proteolytic systems. Recent clinical studies have shown that the promotion of plasmin can lead to an immunosuppressed phenotype, in part via its ability to modulate cytokine expression. Almost all immune cells harbor at least one of a dozen plasminogen receptors that allows plasmin formation on the cell surface that in turn modulates immune cell behavior. Similarly, a multitude of pathogens can also express their own plasminogen activators, or contain surface proteins that provide binding sites host plasminogen. Plasmin formed under these circumstances also empowers these pathogens to modulate host immune defense mechanisms. Phylogenetic studies have revealed that the plasminogen activating system predates the appearance of fibrin, indicating that plasmin did not evolve as a fibrinolytic protease but perhaps has its roots as an immune modifying protease. While its fibrin removing capacity became apparent in lower vertebrates these primitive under-appreciated immune modifying functions still remain and are now becoming more recognised.

Highlights

  • The plasminogen activating (“fibrinolytic”) system is one of the most important proteolytic cascades in all mammals and in a variety of other species

  • While conventionally associated with blood clot removal via the generation of the key protease, plasmin, this system performs a multitude of other important functions, some of which are beginning to impact on clinical medicine

  • Direct evidence is emerging, from animal models, and in humans that the modulation of the plasminogen activating system does impact on immune function

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Summary

Introduction

The plasminogen activating (“fibrinolytic”) system is one of the most important proteolytic cascades in all mammals and in a variety of other species. While conventionally associated with blood clot removal via the generation of the key protease, plasmin, this system performs a multitude of other important functions, some of which are beginning to impact on clinical medicine. Some of these developments, notably on the actions of plasmin on the immune response have been recently reviewed [1]. Direct evidence is emerging, from animal models, and in humans that the modulation of the plasminogen activating system does impact on immune function. This review will discuss the link between the plasminogen activating system with immune function and argue the case that the evolution of this system may have been initially directed at immune modulation but which subsequently became adapted for other functions, including fibrin removal

Plasminogen Activation: A Universal System with a Broad Repertoire
Findings
Phylogenetic Links with Plasminogen Activation
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