Mast Cell CRF2 Suppresses Mast Cell Degranulation and Limits the Severity of Anaphylaxis and Stress-Induced Intestinal Permeability

Publication date: Available online 12 November 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Susan D'Costa, Saravanan Ayyadurai, Amelia J. Gibson, Emily Mackey, Mrigendra Rajput, Laura J. Sommerville, Neco Wilson, Yihang Li, Eric Kubat, Ananth Kumar, Hariharan Subramanian, Aditi Bhargava, Adam J. Moeser

Abstract

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 Kit^W-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 Kit^W-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.

Graphical abstract

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