Publications

Thrombin, a key player in coagulation, is widely held to induce and promote inflamma- tion. As of now, the features, kinetics and control of thrombin’s proinflammatory ef- fects on the skin remain to be characterized in detail. We, therefore, injected thrombin into the ear skin of mice and observed strong, dose-dependent and transient ear swell- ing responses as well as mast cell (MC) degranulation. Unexpectedly, thrombin in- duced even stronger, not reduced, ear swelling in MC-deficient KitW-sh/W-sh mice. Prior local reconstitution of KitW-sh/W-sh mice with MCs inhibited this effect, indicating that MCs may contribute to the control of thrombin-induced skin inflammation. In line with previous studies, we found that MCs express the thrombin receptors PAR1, PAR3 and PAR4, thrombin induces direct and dose-dependent MC degranulation, and that de- granulated MCs inactivate thrombin. Further findings suggested that MC-mediated protection from thrombin-induced inflammation is likely to rely on the effects of MC proteases. We show for the first time that MC-deficient mice and MC protease 4-deficient mice with normal numbers of MCs show markedly increased ear swelling in response to thrombin as compared to wild-type mice. Taken together, these results suggest that thrombin-induced skin inflammation is controlled, in part, by MC pro- tease 4 released from activated MCs. For MC-driven diseases such as chronic sponta- neous urticaria, which has been linked to increased thrombin generation, this might mean that MCs may contribute to the resolution of skin inflammatory responses.