Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor

Shushakova, Nelli; Tkachuk, Natalia; Dangers, Marc; Tkachuk, Sergey; Park, Joon-Keun; Hashimoto, Koji; Haller, Hermann; Dumler, Inna

doi:10.1242/jcs.02409

Cited by 49 publications

(32 citation statements)

References 32 publications

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“…Furthermore, it has recently been shown that C5a induces the expression of plasminogen activatorinhibitor-1 in human mast cells and basophils, thereby affecting the balance between pro-and antifibrinolytic proteins (49). Similarly, cross-talk between the inflammatory and fibrinolytic systems has been suggested by recent studies in which urokinase-type plasminogen activator receptor activation has been shown to up-regulate C5aR expression in human mesangial cells (50). Taken together, these findings support a role for innate immunity, and particularly the C5a/C5aR signaling axis, in the regulation of the early molecular events leading to a disseminated procoagulant response during inflammation.…”

Section: Discussionmentioning

confidence: 96%

A Novel C5a Receptor-Tissue Factor Cross-Talk in Neutrophils Links Innate Immunity to Coagulation Pathways

Ritis

Doumas

Mastellos

et al. 2006

The Journal of Immunology

430

338

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Neutrophils and complement are key sentinels of innate immunity and mediators of acute inflammation. Recent studies have suggested that inflammatory processes modulate thrombogenic pathways. To date, the potential cross-talk between innate immunity and thrombosis and the precise molecular pathway by which complement and neutrophils trigger the coagulation process have remained elusive. In this study, we demonstrate that antiphospholipid Ab-induced complement activation and downstream signaling via C5a receptors in neutrophils leads to the induction of tissue factor (TF), a key initiating component of the blood coagulation cascade. TF expression by neutrophils was associated with an enhanced procoagulant activity, as verified by a modified prothrombin time assay inhibited by anti-TF mAb. Inhibition studies using the complement inhibitor compstatin revealed that complement activation is triggered by antiphospholipid syndrome (APS) IgG and leads to the induction of a TF-dependent coagulant activity. Blockade studies using a selective C5a receptor antagonist and stimulation of neutrophils with recombinant human C5a demonstrated that C5a, and its receptor C5aR, mediate the expression of TF in neutrophils and thereby significantly enhance the procoagulant activity of neutrophils exposed to APS serum. These results identify a novel cross-talk between the complement and coagulation cascades that can potentially be exploited therapeutically in the treatment of APS and other complement-associated thrombotic diseases.

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Section: Discussionmentioning

confidence: 96%

A Novel C5a Receptor-Tissue Factor Cross-Talk in Neutrophils Links Innate Immunity to Coagulation Pathways

Ritis

Doumas

Mastellos

et al. 2006

The Journal of Immunology

430

338

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“…16,21,24,25 Systemic administration of lipopolysaccharide can markedly increase mesangial C5aR expression, which is dependent on urokinase receptor activation. 26 Early in the course of murine lupus nephritis, both C3a and C5a receptor are significantly upregulated, while later in the course of disease, their specific inhibition 16,19 or deletion 27 lessened glomerular disease manifestations. Although not proven directly, it seems most likely mesangial C5a receptor was most relevant in our studies, in spite of its not being upregulated in renal cortex.…”

Section: Discussionmentioning

confidence: 99%

“…Of the many effects that can occur through C5a receptor activation, induction of MCP-1 production, blocking apoptosis and promoting entry into the cell cycle are arguably the most important to our findings here. 26,[28][29][30][31] As the activating proteins in the complement systems of humans and mice are largely comparable, their study in mice can provide useful insights into human pathophysiology. 32 The complement regulators in mice are also largely conserved in humans with some notable differences.…”

Section: Discussionmentioning

confidence: 99%

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Bao

Haas

Minto

et al. 2007

Laboratory Investigation

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The complex balance between the pro-activating and regulatory influences of the complement system can affect the pathogenesis of immune complex-mediated glomerulonephritis (ICGN). Key complement regulatory proteins include decay accelerating factor (DAF) and CD59, which inhibit C3 activation and C5b-9 generation, respectively. Both are glycosylphosphatidylinositol-linked cell membrane proteins, which are widely distributed in humans and mice. Chronic serum sickness induced by daily immunization with horse spleen apoferritin over 6 weeks was used to induce ICGN in DAF-, CD59-and DAF/CD59-deficient mice, with wild-type littermate mice serving as controls. Both DAF and DAF/CD59-deficient mice had an increased incidence of GN relative to wild-type controls associated with significantly increased glomerular C3 deposition. Disease expression in CD59-deficient mice was no different than wild-type controls. DAF-and DAF/CD59-deficient mice also had increased monocyte chemoattractant protein-1 mRNA expression and glomerular infiltration with CD45 þ leukocytes. Our findings suggest that activation of C3 is strongly associated with experimental ICGN while downstream formation of C5b-9 is of lesser pathogenic importance in this model.

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“…The uPAR colocalizes with uPA at focal contacts in the leading edge of migrating cells (26). The uPAR has now been identified on a variety of other cell types, including inflammatory cells (monocytes, macrophages, neutrophils, activated T cells), vascular endothelial cells, epithelial cells (both glomerular and tubular), mesenchymal cells (fibroblasts, myofibroblasts, mesangial cells), and neurons (23,(27)(28)(29)(30)(31)(32). The uPAR, a highly glycosylated 50-kD to 65-kD protein, is a transmembrane receptor with three extracellular domains (D1, D2 and D3) and a single membrane-inserted domain connected to a very short glycosyl-phosphatidylinositol (GPI)-anchored cytoplasmic tail.…”

Section: Functional Overviewmentioning

confidence: 99%

Urokinase and its receptors in chronic kidney disease

Zhang

Eddy

2008

Front Biosci

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Since the recognition that plasminogen activator inhibitor-1 (PAI-1) is a powerful profibrotic molecule, there has been considerable interest in deciphering the extent to which this effect is mediated by its ability to inhibit serine proteases with downstream effects on fibrogenesis. This review will summarize current knowledge about the serine protease urokinase-type plasminogen activator and its high affinity receptor uPAR/CD87 as it pertains to chronic kidney disease (CKD) progression. An emerging theme is that the effects of PAI-1 and uPAR appear to be organ-and site-specific. Normal kidney tubules produce a large quantity of uPA that is secreted into the urinary space. Activity levels increase during CKD presumably due to new sources of production by macrophages and fibroblasts. By activating hepatocyte growth factor and degrading fibrinogen uPA may have anti-fibrotic effects. However CKD severity after experimental ureteral obstruction is not altered by endogenous uPA deficiency. Beneficial effects of exogenous uPA have been reported in experimental models of fibrosis in the lung and liver but CKD awaits exploration.Absent in normal kidneys uPAR is expressed by both renal parenchymal cells and inflammatory cells in a variety of pathological states. Such expression appears beneficial based on studies performed in uPAR-deficient mice. The uPAR promotes bacterial clearance in infectious diseases. In CKD uPAR expression is associated with high uPA activity but its most important effect appears to be due to scavenging activities and effects on cell recruitment and migration. Although uPAR itself is a non-signaling receptor, it interacts with a variety of co-receptors to modify cellular behavior. Best known are interactions with the low-density lipoprotein receptor-related protein (LRP-1) that lead to PAI-1 endocytosis and degradation, and interactions with several integrins to regulate matrix-dependent cell migration. Contacts with the receptor for the complement C5a component and the interleukin −6 receptor gp130 are examples of other recently recognized interactions.In addition to uPA, vitronectin and high molecular weight kininogen are alternate uPAR ligands that could be implicated in CKD progression. uPAR may also be shed from cell membranes. This soluble form (suPAR) has been detected in plasma and urine and is known to be a chemoattractant for leukocytes that express the formyl-peptide-receptor-like receptor

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Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor

Cited by 49 publications

References 32 publications

A Novel C5a Receptor-Tissue Factor Cross-Talk in Neutrophils Links Innate Immunity to Coagulation Pathways

A Novel C5a Receptor-Tissue Factor Cross-Talk in Neutrophils Links Innate Immunity to Coagulation Pathways

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Urokinase and its receptors in chronic kidney disease

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