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

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 Kit^W-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.