BACKGROUND:Psychological stress and heightened MC activation are linked with important immunological disorders including allergy, anaphylaxis, asthma, and functional bowel diseases, but the mechanisms remain poorly defined. We have previously demonstrated that activation of the corticotropin releasing factor (CRF) system potentiates MC degranulation responses during IgE-mediated anaphylaxis and psychological stress, via CRF receptor subtype 1 (CRF1) expressed on MCs. OBJECTIVE:In this study, we investigated the role of CRF receptor subtype 2 (CRF2) as a modulator of stress-induced MC degranulation and associated disease pathophysiology. METHODS:In vitro MC degranulation assays were performed with bone marrow derived MCs (BMMCs) derived from WT and CRF2-deficient (CRF2-/-) mice and RBL-2H3 MCs transfected with CRF2-overexpressing plasmid or CRF2-siRNA. In vivo MC responses and associated pathophysiology in IgE-mediated passive systemic anaphylaxis (PSA) and acute psychological restraint stress were measured in WT, CRF2-/-, and MC-deficient KitW-sh/W-sh knock-in mice. RESULTS:Compared with WT mice, CRF2-/- exhibited heightened serum histamine levels and exacerbated PSA-induced anaphylactic responses and colonic permeability. In addition, CRF2-/- mice exhibited increased serum histamine and colonic permeability following acute restraint stress. Experiments with BMMCs and RBL-2H3 MCs demonstrated that CRF2 expressed on MCs suppresses store-operated Ca2+ entry (SOCE) signaling and MC degranulation induced by diverse MC stimuli. Experiments with MC-deficient KitW-sh/W-sh mice systemically engrafted with WT and CRF2-/- BMMCs demonstrated the functional importance of MC-CRF2 in modulating stress-induced pathophysiology. CONCLUSIONS:MC CRF2 is a negative, global modulator of stimuli-induced MC degranulation and limits the severity of IgE-mediated anaphylaxis and stress-related disease pathogenesis.