肥大细胞促肾上腺皮质素释放因子 2 型抑制肥大细胞脱颗粒，限制过敏反应和应激诱导的肠道通透性的严重程度。
Mast cell corticotropin-releasing factor subtype 2 suppresses mast cell degranulation and limits the severity of anaphylaxis and stress-induced intestinal permeability.
机构信息
Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC.
Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, East Lansing, Mich.
出版信息
J Allergy Clin Immunol. 2019 May;143(5):1865-1877.e4. doi: 10.1016/j.jaci.2018.08.053. Epub 2018 Nov 12.
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.
背景
心理压力和肥大细胞（MC）激活与重要的免疫紊乱有关，包括过敏、过敏反应、哮喘和功能性肠病，但机制仍不清楚。我们之前的研究表明，在 IgE 介导的过敏反应和心理压力期间，促肾上腺皮质释放因子（CRF）系统的激活通过 MC 上表达的 CRF 受体亚型 1（CRF1）增强 MC 脱颗粒反应。
目的
在这项研究中，我们研究了 CRF 受体亚型 2（CRF2）作为应激诱导的 MC 脱颗粒和相关疾病发病机制的调节剂的作用。
方法
采用骨髓来源的肥大细胞（BMMC）进行体外 MC 脱颗粒测定，这些细胞来自野生型（WT）和 CRF 缺陷（CRF）小鼠以及转染了 CRF 过表达质粒或 CRF 小干扰 RNA 的 RBL-2H3 MC。在 IgE 介导的被动全身过敏反应和急性心理束缚应激中，测量 WT、CRF 和 MC 缺陷 Kit 基因敲入小鼠中的 MC 反应和相关病理生理学变化。
结果
与 WT 小鼠相比，CRF 小鼠表现出更高的血清组胺水平和更严重的 IgE 介导的过敏反应和结肠通透性增加。此外，CRF 小鼠在急性束缚应激后表现出更高的血清组胺水平和结肠通透性增加。BMMC 和 RBL-2H3 MC 的实验表明，MC 上表达的 CRF 抑制了各种 MC 刺激诱导的储存操纵性 Ca 内流信号和 MC 脱颗粒。用系统移植了 WT 和 CRF BMMC 的 MC 缺陷 Kit 小鼠进行的实验表明，MC CRF 在调节应激诱导的病理生理学方面具有重要功能。
结论
MC CRF 是刺激诱导的 MC 脱颗粒的负全局调节剂，限制了 IgE 介导的过敏反应和应激相关疾病发病机制的严重程度。
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