uPA, uPAR and suPAR IN INFLAMMATION
Inflammation is the reaction of a vascularized tissue to a pathogenic insult i.e., trauma, infectious agent, foreign particle, ischemia or neoplasm. It is characterized by the generation of inflammatory mediators, by increased vascular permeability and by migration of leukocytes into extravascular tissues.
The primary purpose of the inflammatory response is to eliminate the pathogenic insult and remove injured tissue components. Ideally, the result of the inflammatory response is resolution in which the pathogenic insult is eliminated, the inflammatory response is resolved and normal tissue architecture and physiological function is restored. Thus, tissue repair and remodelling always accompany the inflammatory response. If the immune cells fail to eliminate the source of tissue injury, the inflammatory reaction persists, leading to chronic inflammation.The inflammatory response begins as the result of direct injury or stimulation of the cellular and structural components of the tissue, including parenchymal cells, microvasculature, tissue macrophages and mast cells, fibroblasts, smooth muscle cells and the ECM. Inflammatory mediators produced at the site of injury regulate the response of the vasculature to injury (by production of vasoactive molecules) and the recruitment of leukocytes (by production of chemotactic factors). uPA, uPAR and suPAR are all intimately involved in the inflammatory response and may therefore be good markers of the inflammatory state of the individual.
Inflammatory Mediators
Inflammatory mediators produced in response to tissue injury include vasoactive mediators, chemotactic mediators and cytokines that regulate expression and release of uPAR in immune cells and tissue cells.
Many bacterial components (LPS, muramyl dipeptide, lipoteichoic acid, Staphylococcal enterotoxin B, heat killed Staphylococcus aureus, lipoarabinomannan, Tuberculin purifed protein derivate, viable/heat killed Borrelia Burgdorferi) and HIV-1 enhance uPAR-expression in vitro in monocyte-like cells [23,107,119-122], granulocytes [121] and T cells [55,107].
Furthermore, LPS, lipoteichoic acid and B. Burgdorferi enhance uPAR-release in monocyte-like cells [120,122]. Endotoxemia induced by IV injection of endotoxin enhances uPAR-expression in vivo in monocytes [23,121] and granulocytes [121] and increases the level of suPAR in plasma [17,23,118] and urine [17]. Even low-dose endotoxemia enhances uPAR-release from cultured PBMC [22]. However, it should be noted that suPAR does not show acute phase protein dynamics such as C-reactive protein (CRP). While CRP is a highly inducible acute phase protein, suPAR does not show major variation in blood. Infusion with 2 ng/kg LPS in human subjects lead to less than 2-fold increase in plasma suPAR level [22] and in contrast to many pro-inflammatory cytokines, circadian suPAR levels (measured every 20 minutes for 24 hours) have been shown to be quite constant [123]. C5a enhances uPAR-expression in vitro in monocyte-like cells [124] and many cytokines (TNF-α, IFN-γ, IL-1β, IL-2, IL-6, IL-7, IL-8) enhance uPAR- expression in vitro in monocyte-like cells [23,124-126], granulocytes [111,127], T cells [55], NK cells [128] and vascular endothelial cells [60]. Furthermore, TNF-α and IL-1β enhance uPAR-release in vitro in monocyte-like cells, granulocytes and vascular endothelial cells [60,126,127]. In contrast, IL-4 and TGF-β can downregulate uPAR-expression in vitro in T cells [55] and IL-4, IL-10 and IL-13 can downregulate uPAR- expression and release in vitro in monocyte-like cells [129]. It should be noted that studies investigating uPA binding capacity as a marker of the amount of uPAR protein at the cell surface [55,124,125] may underestimate uPAR-expression because the cleaved receptor (uPAR(II-III)) is unable to bind uPA.Vascular Permeability
The vascular mediators exert their effect by binding to specific receptors on vascular endothelial and smooth muscle cells. Vascular mediators induce vasodilatation and contraction of endothelial cells resulting in endothelial gap formation and increased permeability of the endothelial cell barrier.
The loss of endothelial cell integrity leads to leakage of fluid and plasma components and emigration of erythrocytes and leukocytes from the vascular compartment to the extravascular compartment.Expression of uPAR on endothelial cells may modulate vascular permeability as uPA binding and plasmin generation at the surface of endothelial cells induces loss of cell-cell contacts, retraction of endothelial cells and increased permeability [130]. Also, uPAR is indirectly involved in generation of uPA-catalyzed vasoactive mediators (plasmin, degradation products of fibrin). Several vasoactive mediators affect uPAR by enhancing uPAR-expression in immune cells (C5a) [124] or by cleaving the receptor between uPAR(I) and uPAR(II) (plasmin) [64].
Tissue Repair and Remodelling
Tissue repair is part of the inflammatory response and represents an attempt to maintain normal structure and function. Protease activity is essential for the tissue remodelling process [2,3,7,78,131,132]. Thus, plasminogen-deficient mice have impaired wound healing [131] and inhibition of MMPs in plasminogendeficient mice completely arrests wound healing and wound closure [132].
As a cellular receptor for uPA, uPAR is involved in ECM degradation during physiological processes with tissue remodelling and tumour cell invasion. Accordingly, in mice, uPAR is highly expressed in tissues undergoing extensive remodelling such as trophoblast cells in placenta, migrating keratinocytes at the edge of incisional wounds and granulocytes infiltrating the area beneath the wound crust [131,133-135]. In addition to ECM degradation, plasmin and uPA both activate and release various growth factors, cytokines and chemokines of importance for tissue repair, remodelling and cell recruitment [3,5,6,8,40,63,136] and (s)uPAR(II-III) may recruit immune cells to the site of injury thus enhancing the tissue remodelling process [8].