Corticotropin releasing factor receptor 2 exerts global suppression of mast cell degranulation and associated pathophysiology.

Abstract

Psychological stress triggers mast cell (MC) activation and is a major risk factor in the onset and exacerbation of MC-associated disorders including allergy/anaphylaxis, irritable bowel syndrome, and autoimmune diseases. The mechanisms by which stress modulates MC function and disease susceptibility is poorly understood. Our previous studies showed that corticotropin releasing factor receptor 1 (CRF₁) signaling potentiated stress-induced MC degranulation. Here we utilized CRF₂ deficient (CRF₂ ^−/−) mice and MCs to define the in vivo and in vitro biological importance of CRF receptor subtype 2, CRF₂. Compared with WT mice, CRF₂ ^−/− mice exhibited greater serum histamine levels following restraint stress (RS) (by 143%) and IgE-mediated passive systemic anaphylaxis (PSA) (by 415%). The heightened response was greater in CRF₂ ^−/− females compared with males. CRF₂ ^−/− mice exhibited greater RS-induced and PSA-induced elevations in intestinal permeability compared to WT mice. Bone marrow derived MCs (BMMCs) derived from CRF₂ ^−/− mice exhibited greater release of β-hexosaminidase and histamine and heightened Ca²⁺ mobilization from intracellular stores in response to diverse MC stimuli including IgE/DNP, c48/80, and A23187. MC-deficient mice engrafted with CRF₂ ^−/− BMMCs exhibited greater RS-induced intestinal permeability and PSA-induced hypothermia compared with WT BMMC-engrafted mice. Together, these results demonstrate that MC-CRF₂ receptor signaling exerts a global suppression of MC degranulation and pathophysiology. Elucidation of the mechanisms by which CRF₂ dampens MC degranulation could reveal novel therapeutic targets for hyperactive MC disorders.