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

Abstract

Mast cell corticotropin-releasing factor subtype 2 suppresses mast cell degranulation and limits the severity of anaphylaxis and stress-induced intestinal permeability. Permalink https://escholarship.org/uc/item/8t3660m4 Journal Abstract 33 34 Background: Psychological stress and heightened MC activation are linked with important 35 immunological disorders including allergy, anaphylaxis, asthma, and functional bowel 36diseases, but the mechanisms remain poorly defined. We have previously demonstrated that 37 activation of the corticotropin releasing factor (CRF) system potentiates MC degranulation 38 responses during IgE-mediated anaphylaxis and psychological stress, via CRF receptor 39 subtype 1 (CRF 1 ) expressed on MCs. 40 41 Objective: In this study, we investigated the role of CRF receptor subtype 2 (CRF 2 ) as a 42 modulator of stress-induced MC degranulation and associated disease pathophysiology. 43 44 Methods: In vitro MC degranulation assays were performed with bone marrow derived MCs 45 (BMMCs) derived from WT and CRF 2 -deficient (CRF 2 -/-) mice and RBL-2H3 MCs transfected 46 with CRF 2 -overexpressing plasmid or CRF 2 -siRNA. In vivo MC responses and associated 47 pathophysiology in IgE-mediated passive systemic anaphylaxis (PSA) and acute 48 psychological restraint stress were measured in WT, CRF 2 -/-, and MC-deficient Kit W-sh/W-sh 49 knock-in mice. 50 51 Results: Compared with WT mice, CRF 2 -/exhibited heightened serum histamine levels and 52 exacerbated PSA-induced anaphylactic responses and colonic permeability. In addition, 53 CRF 2 -/mice exhibited increased serum histamine and colonic permeability following acute 54 restraint stress. Experiments with BMMCs and RBL-2H3 MCs demonstrated that CRF 2 55 expressed on MCs suppresses store-operated Ca 2+ entry (SOCE) signaling and MC 56 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 3 degranulation induced by diverse MC stimuli. Experiments with MC-deficient Kit W-sh/W-sh mice 57 systemically engrafted with WT and CRF 2 -/-BMMCs demonstrated the functional importance 58 of MC-CRF 2 in modulating stress-induced pathophysiology. 59 60 Conclusions: MC CRF 2 is a negative, global modulator of stimuli-induced MC degranulation 61 and limits the severity of IgE-mediated anaphylaxis and stress-related disease pathogenesis. 62 63 Key messages 64 • Loss of CRF 2 function induces exacerbated MC degranulation, IgE-mediated 65 anaphylaxis and psychological stress-induced intestinal barrier dysfunction. 66 • MC-specific CRF 2 suppresses degranulation induced by diverse MC stimuli via 67 negative regulation of SOCE. 68 • Further characterization of the mechanisms by which CRF 2 negatively modulates MC 69 activation could lead to novel therapeutic approaches for stress-related immunological 70 disorders associated with MC hyperactivity. 71 72

Plasma Corticotropin-Releasing Factor Receptors and B7-2+ Extracellular Vesicles in Blood Correlate with Irritable Bowel Syndrome Disease Severity

“…We have recently shown presence of CRF receptors on mast cells [18], enteric neurons, pancreatic acinar cells [16], and fibroblasts [29]. We have also shown increased mast cell infiltration in the gut in a rat model of functional dyspepsia, a gut-brain disorder [19].…”

“…CRF 1 activation initiates HPA responses and anxiety-like behavior, whereas CRF 2 activation brings systems back to homeostasis, and mediates anxiolytic behavior [11,12]. We have shown that CRF 2 plays a vital role in mediating metabolic [13] and immune responses [14,15,16,17,18,19]. CRF 2 receptor dysfunction is known to exacerbate edema, necrosis, and delayed healing [14,20].…”

“…CRFRs belong to the Class B secretin receptor family of GPCRs. Various cell-types and tissues synthesize and express CRFR [15,16,18,24,29,30]. CRFR mediate both autocrine and paracrine responses [31], and thus, it is reasonable to speculate that they might be secreted in to the circulation from various cells and tissues.…”

Mast Cells in Gut and Brain and Their Potential Role as an Emerging Therapeutic Target for Neural Diseases

“…In addition, they contain vast CRF stores (Theoharides and Konstantinidou, 2007). A recent study showed that CRF2 represents a negative modulator of MC activation, suggesting a crucial homeostatic role of MC in the CRF system and in the disorders associated with his (D’Costa et al, 2019).…”

Environmental stressors affect intestinal permeability and repair responses in a pig intestinal ischemia model

“…14,25 Blockade of peripheral CRF receptors or treatment with mast cell stabilizers will block these effects on the intestinal barrier, confirming the role of mast cells in altering barrier permeability following physical and psychological stress. 14,19,37 Mast cell activation induced by stress could play a key role in the effects seen in the present study, and it is likely that it takes longer than a brief period of transport for these responses to take place. As these barrier effects follow the upregulation of mucosal CRF localized to mast cells, which may also need time to marginate into the tissue from circulation, mast cell responses to stress may partly explain why intestinal barrier repair responses are different in the period immediately after a brief transport stress as compared to more prolonged environmental change over several days.…”