Mast Cell Corticotropin Releasing Factor Receptor Subtypes Play Opposing Roles in Mediating Stress‐Induced Colonic Barrier Dysfunction

Abstract

It has long been known that gastrointestinal disorders are profoundly influenced by life stress; however the mechanisms are poorly understood. Previous research showed that psychological stress causes disturbances in intestinal epithelial barrier function via corticotropin releasing factor (CRF)‐dependent activation of intestinal mast cells (MC). The precise pathway of MC activation by CRF in the stress response remains unclear. Here we definitively explore the role of MC CRF receptors 1 and 2 (CRF1 and CRF2) in stress‐induced intestinal barrier dysfunction. MC‐deficient mice (W‐sh/W‐sh) were repleted with bone marrow‐derived mast cells (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). Transepithelial electrical resistance (TER) and paracellular flux of FITC‐dextran (FD4) were measured in Ussing chambers as indices of barrier function. There was a significant increase (p=0.003) in the rate of FD flux and reduction in TER in the colon of WT mice subjected to RS but not in W‐sh/W‐sh mice. Repletion of W‐sh/W‐sh mice with WT BMMCs restored stress‐induced changes in FD4 flux and TER (p=0.01). 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). These data definitively show that MC CRF1 mediates stress‐induced intestinal barrier dysfunction while CRF2 may play a critical barrier protective role. These opposing roles of CRF receptors may help in identifying novel preventative and therapeutic targets to mitigate stress‐related intestinal disorders.