Mast Cells Regulation of Homeostatic Intestinal Barrier Function is dependent on the Human Chymase Homologue, mcpt4.

Abstract

Disruption of the intestinal epithelial barrier has been proposed to be a central predisposing factor to intestinal diseases, however the molecular mechanisms involved in the maintenance of homeostatic intestinal epithelial barrier integrity has not been defined. We demonstrate a decrease in paracellular and transcellular intestinal permeability in mast cell (MC)‐deficient KitW‐sh/W‐sh mice as compared to C57Bl/6 WT mice (paracellular [Dextran‐FITC]: 172.3 ± 35.3 vs 378.1 ± 54.3 ng/ml; p < 0.005; transcellular [HRP]: 0.0079 ± 0.0036 vs 1.1129 ± 0.4798 ng/ml; p < 0.05). We confirm MC involvement in homeostatic intestinal barrier function as reconstitution of bone marrow derived mast cells (BMMC's) into KitW‐sh/W‐sh mice restored intestinal epithelial barrier integrity. Importantly, we identified that MC‐regulation of homeostatic intestinal barrier function was dependent on MC protease 4 (mcpt4). Moreover, mcpt‐4−/− mice intestinal epithelial barrier integrity was decreased as compared to WT mice ([Dextran‐FITC]: 115.3 ± 25.2 vs 378.1 ± 54.3 ng/ml; p < 0.005; [HRP]: 0.179 ± 0.1306 vs 1.1129 ± 0.4798 ng/ml; p < 0.05), to levels equivalent to that of KitW‐sh/W‐sh mice. Furthermore, reconstitution of mcpt4−/− BMMC's into KitW‐sh/W‐sh mice did not restore intestinal epithelial barrier integrity. Collectively, our data demonstrates a critical role for MC's in the regulation of homeostatic intestinal barrier function.