Role of viral receptors TLR3, RIG-I and MDA5 in mesothelial tissue-type plasminogen activator and plasminogen activator inhibitor-1 synthesis

Summary Tissue-type plasminogen activator (t-PA) and its specific inhibitor plasminogen activator inhibitor-1 (PAI-1) are key mediators in the regulation of fibrin generation and fibrinolysis. Mesothelial cells (MC) line the inner surface of serosal cavities and are a source of procoagulant and fibrinolytic system components. Viral inflammation and infection of MC are a major problem in several organ systems including pleura, pericardium and peritoneum. MC express the viral receptors Toll-like receptor 3 (TLR3), RIG-I and MDA5. TLRs recognise molecular patterns associated with microbial pathogens and induce an immune response. TLR3 recognises dsRNA of viral origin as exemplified by poly (I:C) RNA, a synthetic analogue of viral dsRNA. The helicases RIG-I and MDA5 may also act as sensors of viral infections. Activation of these receptors by poly (I:C) RNA leads to an time- and dose-dependent increase of mesothelial PAI-1 synthesis and a decrease of t-PA expression. To show the specific effect of viral receptors knockdown experiments with siRNA specific for TLR3, RIG-I and MDA5 were performed. This finding of viral induced changes of t-PA and PAI-1 synthesis may indicate a novel link between viral infections and formation of mesothelial fibrin deposits and progression of viral associated disease of the pleura, peritoneum and pericardium.