Mast cell corticotropin-releasing factor subtype 2 suppresses mast cell degranulation and limits the severity of anaphylaxis and stress-induced intestinal permeability.

Background: Psychological stress and heightened mast cell (MC) activation are linked with important immunologic 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 through corticotropin-releasing factor receptor subtype 1 (CRF) expressed on MCs.

Objective: In this study we investigated the role of corticotropin-releasing factor receptor subtype 2 (CRF) as a modulator of stress-induced MC degranulation and associated disease pathophysiology.

Methods: In vitro MC degranulation assays were performed with bone marrow-derived mast cells (BMMCs) derived from wild-type (WT) and CRF-deficient (CRF) mice and RBL-2H3 MCs transfected with CRF-overexpressing plasmid or CRF small interfering RNA. In vivo MC responses and associated pathophysiology in IgE-mediated passive systemic anaphylaxis and acute psychological restraint stress were measured in WT, CRF, and MC-deficient Kit knock-in mice.

Results: Compared with WT mice, CRF mice exhibited greater serum histamine levels and exacerbated IgE-mediated anaphylaxis and colonic permeability. In addition, CRF mice exhibited increased serum histamine levels and colonic permeability after acute restraint stress. Experiments with BMMCs and RBL-2H3 MCs demonstrated that CRF expressed on MCs suppresses store-operated Ca entry signaling and MC degranulation induced by diverse MC stimuli. Experiments with MC-deficient Kit mice systemically engrafted with WT and CRF BMMCs demonstrated the functional importance of MC CRF in modulating stress-induced pathophysiology.

Conclusions: MC CRF is a negative global modulator of stimuli-induced MC degranulation and limits the severity of IgE-mediated anaphylaxis and stress-related disease pathogenesis.