Roles of the tissue-type plasminogen activator in immune response

Abstract

The COVID-19 pandemic has once again brought to the forefront the existence of a tight link between the coagulation/fibrinolytic system and the immunologic processes. Tissue-type plasminogen activator (tPA) is a serine protease with a key role in fibrinolysis by converting plasminogen into plasmin that can finally degrade fibrin clots. tPA is released in the blood by endothelial cells and hepatocytes but is also produced by various types of immune cells including T cells and monocytes. Beyond its role on hemostasis, tPA is also a potent modulator of inflammation and is involved in the regulation of several inflammatory diseases. Here, after a brief description of tPA structure, we review its new functions in adaptive immunity focusing on T cells and antigen presenting cells. We intend to synthesize the recent knowledge on proteolysis- and receptor-mediated effects of tPA on immune response in physiological and pathological context.

Keywords: Antigen presenting cells; Immunopathology; Macrophages; Plasmin; Plasminogen activation system; T cells; Tissue-type plasminogen activator.

Fig. 1

Effects of the plasminogen activation system on migration and adhesion of immune cells. tPA is involved in the recruitment of immune cells by promoting the release of chemokines (A and B). tPA increases the expression of the adhesion molecule ICAM1 on endothelial cells by acting on the LRP1 receptor (C). tPA-NMDAR binding on endothelial cells facilitates diapedesis of leucocytes (D). The monoclonal antibody Glunomab limits the leucocyte infiltration by blocking the interaction between tPA and NMDAR.

Fig. 2

Effects of the plasminogen activation system on T cell functions. tPA increases MHC-II and costimulatory CD80 and CD86 molecule expression on antigen presenting cells (dendritic cells and macrophages) by the binding of the EGF-R. T cell activation and proliferation is enhanced by tPA through its proteolytic action (A). tPA increases the production of the proinflammatory cytokines IFN-γ and IL-17 (B). tPA contributes to the T cell clustering by a plasmin dependent mechanism. This effect is reversed by neuroserpin (C).

Fig. 3

Effects of the plasminogen activation system on mononuclear phagocyte cells. tPA promotes the clearance of apoptotic cells by dendritic cells (A). tPA is involved in the polarization of macrophages (B). tPA may have opposite effects on macrophage activation. tPA, as a plasmin activating protease, has a proinflammatory effects whereas tPA exerts anti-inflammatory effects via the binding to the NMDAR and LRP1 receptors.