Anaphylatoxin receptor C3aR on platelets participates in platelet function and links innate immunity with thrombosis

Abstract

Abstract Background Beyond the superficial function of blood coagulation, platelets play an important role in the genesis of vascular inflammatory processes. Interestingly, platelets express the complement receptor C3aR. Here, we examine the role of the complement receptor C3aR on platelets for platelet function and in diseases. Methods We detected the expression of C3aR on murine and human platelets using western blot and flow cytometry. We examined proteins, that are in close connection to the C3aR receptor on platelets by mass spectrometry to elucidate the intracellular signaling. We examined the role of the platelet C3aR for platelet function using different platelet function tests. To investigate the relevance of our findings in vivo, we made use of mice that are deficient for C3aR. After performing bleeding time and intravital microscopy experiments, we induced myocardial infarction and stroke in knockout animals. Results We found that C3aR on platelets plays an important role in platelet function and thrombus formation. We discovered that the complement activation fragment C3a regulates bleeding time after tail injury and thrombosis using C3aR−/− mice or C3−/− mice with re-injection of C3a. After induction of a myocardial infarction or stroke in mice, C3aR−/− mice showed a better outcome in comparison to WT mice. When analyzing the intracellular signaling, we discovered that those effects were PI3 kinase and Rap-1 dependent. Conclusions Taken together, we identified the C3a receptor on platelets as an important player in platelet function and thrombus formation. Linking the systems of innate immunology and hemostasis, the C3a receptor on platelets could be a possible therapeutic target in diseases featuring thromboinflammation.