Mast cell corticotropin releasing factor receptor CRF2 regulates mast cell function in response to psychological and immunological stress

Abstract

Abstract Psychological stress is a significant risk factor in a number of inflammatory and allergic diseases. We have previously demonstrated that CRF1 receptors expressed on mast cells (MCs) can potentiate psychological stress-induced MC degranulation intestinal permeability, and IgE-mediated anaphylaxis. In this study, we investigated the role of the CRF2 receptors in regulating MC activation in response to psychological and immunological stress. CRF2-deficient (CRF2−/−) bone marrow derived MCs exhibited enhanced IgE-and c48/80-mediated mast cell degranulation, determined by β-hex and histamine release. Heightened degranulation in CRF2−/− MCs were mediated by enhanced intracellular Ca2+ mobilization from endoplasmic reticulum stores. Similar results were obtained with human LAD2 mast cells treated with the CRF2 antagonist Astressin 2B. In vitro findings translated to in vivo studies as MC-deficient KitW-sh/W-sh mice systemically engrafted with CRF2−/− BMMCs exhibited a 3-fold increase in serum histamine levels and intestinal permeability following acute restraint stress or passive systemic anaphylaxis. Contrasting effects of CRF2 were observed with de novo synthesized mediator release as IL-4, IL-6, MCP-1 and prostaglandin D2 release were reduced (by ~40–50%) in CRF2−/− BMMCs following stimulation with IgE-antigen, LPS and IL-33. In summary, these data show that CRF2 signaling inhibits MC degranulation and associated pathophysiology induced by acute psychological stress and IgE-mediated anaphylaxis, while enhancing the release of de novo synthesized mediators. Therefore, targeting CRF2 may represent a novel therapeutic approach for preventing stress-related allergic and inflammatory disease flares.