Mast cell CRF receptor subtypes differentially modulate mast cell signaling and epithelial barrier injury during stress.

Abstract

Debilitating GI diseases, including irritable bowel syndrome (IBS) and the inflammatory bowel diseases (IBD), are initiated and exacerbated by life stress. It is known that intestinal mast cells (MC) play a critical effector role in stress‐related diseases; however, the precise signaling pathways remain poorly understood. The objective of this research was to elucidate the role of MC corticotropin releasing factor (CRF) receptors in stress‐induced MC activation and intestinal epithelial barrier injury. MC‐deficient mice (W‐sh/ W‐sh) were repleted with bone marrow‐derived MC (BMMCs) from wild type (WT), CRF1KO, or CRF2 KO mice. Following the successful repletion of BMMCs, mice were subjected to 3 hours of restraint stress (RS) and intestinal permeability, in terms of FITC 4kDa dextran (FD4) flux, was measured. Repletion of W‐sh/ W‐sh mice with CRF1 KO BMMCs ameliorated stress‐induced increases in FD4 flux. In contrast, repletion of W‐sh/ W‐sh mice with CRF2 KO BMMCS exacerbated stress‐induced barrier dysfunction compared with WT BMMC controls (p<0.05). Compared with WT BMMCs, CRF2 KO BMMCs exhibited greater intracellular Ca++ elevations and tryptase release in response to A23187. CRF2 KO BMMCs exhibited greater p44/42 activation and cAMP levels in response to CRF (0.5uM). These data show that MC CRF1 and CRF2 differentially modulate mast cell activation and intestinal barrier injury. This work was funded by NIH grant K08 DK084313 (A.J.M.).