Barra Jasmine, Liwski Christopher R, Phonchareon Phoebe, Portales-Cervantes Liliana, Gaston Daniel, Karakach Tobias K, Haidl Ian D, Marshall Jean S
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada; Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada.
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
J Allergy Clin Immunol. 2025 Jun;155(6):1968-1980. doi: 10.1016/j.jaci.2025.02.025. Epub 2025 Feb 28.
Mast cells are important sentinel cells in defense against mucosal infection. Exacerbations of allergic asthma and asthma deaths have been associated with respiratory viral infections. Elevated levels of IL-5 have been associated with the pathogenesis of severe atopic diseases, many of which respond to IL-5 blockade.
We sought to examine the impact of IL-5 signaling on mast cells infected with respiratory viruses.
Cord blood-derived human mast cells were treated with IL-5 or left untreated and infected with human coronavirus OC43, respiratory syncytial virus (RSV), or oncolytic reovirus. Mast cell expression of interferons and of interferon-stimulated genes was evaluated. Total RNA sequencing was performed to determine the impact of IL-5 on the transcriptome of human mast cells, and related functional assays were performed.
IL-5-treated mast cells produced significantly more type I and III interferons than did controls not treated with IL-5. Mechanistically, IL-5 treatment led to greater expression of the prosurvival factor B-cell lymphoma 2 (BCL2) and endothelial PAS domain protein 1 (EPAS1) and protected mast cells from apoptosis-induced stress. IL-5 blockade was associated with a decrease in EPAS1 expression in the peripheral blood of asthmatic patients, as shown by transcriptomic data from clinical trials of mepolizumab and benralizumab.
IL-5 signaling selectively promotes interferon responses in mast cells and maintains mast cell populations during mucosal viral infection via a novel IL-5/EPAS1 axis.
肥大细胞是抵御黏膜感染的重要哨兵细胞。过敏性哮喘的发作和哮喘死亡与呼吸道病毒感染有关。白细胞介素-5（IL-5）水平升高与严重特应性疾病的发病机制有关，其中许多疾病对IL-5阻断有反应。
我们试图研究IL-5信号传导对感染呼吸道病毒的肥大细胞的影响。
用人IL-5处理脐血来源的人肥大细胞或不进行处理，然后用人类冠状病毒OC43、呼吸道合胞病毒（RSV）或溶瘤呼肠孤病毒感染。评估肥大细胞中干扰素和干扰素刺激基因的表达。进行全RNA测序以确定IL-5对人肥大细胞转录组的影响，并进行相关功能测定。
与未用IL-5处理的对照相比，用IL-5处理的肥大细胞产生的I型和III型干扰素明显更多。从机制上讲，IL-5处理导致促生存因子B细胞淋巴瘤2（BCL2）和内皮PAS结构域蛋白1（EPAS1）的表达增加，并保护肥大细胞免受凋亡诱导的应激。如美泊利单抗和贝那利珠单抗临床试验的转录组数据所示，IL-5阻断与哮喘患者外周血中EPAS1表达的降低有关。
IL-5信号传导选择性地促进肥大细胞中的干扰素反应，并通过新的IL-5/EPAS1轴在黏膜病毒感染期间维持肥大细胞群体。
