Mast cells are critical for the limitation of thrombin-induced skin inflammation

Abstract

Thrombin, a key player in coagulation, is widely held to induce and promote inflammation. As of now, the features, kinetics, and control of thrombin's proinflammatory effects 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 swelling responses as well as mast cell degranulation. Unexpectedly, thrombin induced even stronger, not reduced, ear swelling in mast cell-deficient Kit^W-sh/W-sh mice. Prior local reconstitution of Kit^W-sh/W-sh mice with mast cells inhibited this effect, indicating that mast cells may contribute to the control of thrombin-induced skin inflammation. In line with previous studies we found that mast cells express the thrombin receptors PAR1, PAR3 and PAR4, thrombin induces direct and dose-dependent mast cell degranulation and that degranulated mast cells inactivate thrombin. Further findings suggested that MC-mediated protection from thrombin-induced inflammation is likely to rely on the effects of mast cell proteases. We show for the first time, that mast cell-deficient mice and mast cell 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 mast cell protease 4 released from activated mast cells. For MC-driven diseases such as chronic spontaneous urticaria, which has been linked to increased thrombin generation, this might mean that MCs may contribute to the resolution of skin inflammatory responses.

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