多组学分析发现，IL-4 诱导的 IL1RL1 高嗜酸性粒细胞具有突出的半胱氨酰白三烯代谢特征。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology Pub Date : 2024-11-01 DOI:10.1016/j.jaci.2024.07.012

Keeya Sunata MD , Jun Miyata MD, PhD , Yusuke Kawashima PhD , Ryo Konno PhD , Masaki Ishikawa PhD , Yoshinori Hasegawa PhD , Ryuta Onozato MD , Yo Otsu MD , Emiko Matsuyama MD , Hisashi Sasaki MD , Shinichi Okuzumi MD, PhD , Takao Mochimaru MD, PhD , Katsunori Masaki MD, PhD , Hiroki Kabata MD, PhD , Akihiko Kawana MD, PhD , Makoto Arita PhD , Koichi Fukunaga MD, PhD

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引用次数: 0

摘要

背景：临床研究表明，2型细胞因子IL-4在慢性鼻炎（CRS）和嗜酸性粒细胞性哮喘（EA）的发病机制中发挥着重要作用。然而，IL-4 对嗜酸性粒细胞的直接影响仍不清楚：我们旨在阐明 IL-4 对人类嗜酸性粒细胞功能的炎症影响：方法：使用IL-4、IL-5或它们的组合刺激健康受试者的血液嗜酸性粒细胞，进行包括转录组学、蛋白质组学、脂质组学、定量RT-PCR和流式细胞术在内的多组学分析：结果：转录组学和蛋白质组学分析表明，IL-4和IL-5都能上调γ-谷氨酰转移酶5（GGT5）的表达，GGT5是一种脂肪酸代谢酶，能将白三烯C4（LTC4）转化为LTD4。此外，IL-4 还能特异性上调 IL1RL1（IL-33 的受体）和转谷氨酰胺酶 2（TGM2）的表达。对受到 IL-13 刺激的细胞进行的其他转录组分析显示，基因表达谱发生了改变，其特征是 GGT5、TGM2 和 IL1RL1 的上调。IL-13 诱导的变化与 IL-4 诱导的变化没有完全不同。脂质体分析表明，IL-5和IL-4会增加细胞外LTD4的释放。体外实验显示，STAT6和IL-4受体α能在IL-4和IL-13存在的情况下控制这些分子的表达。对过敏性疾病患者嗜酸性粒细胞的分析表明，IL-4和IL-13参与了炎症部位的活动：IL-4通过STAT6诱导IL1RL1高的嗜酸性粒细胞形成促过敏表型，并具有突出的半胱氨酰白三烯代谢。这些细胞变化是 CRS 和 EA 的潜在治疗目标。

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Multiomics analysis identified IL-4–induced IL1RL1high eosinophils characterized by prominent cysteinyl leukotriene metabolism

Background

Clinical studies have demonstrated that IL-4, a type 2 cytokine, plays an important role in the pathogenesis of chronic rhinosinusitis and eosinophilic asthma. However, the direct effect of IL-4 on eosinophils remains unclear.

Objective

We aimed to elucidate the inflammatory effects of IL-4 on the functions of human eosinophils.

Methods

A multiomics analysis comprising transcriptomics, proteomics, lipidomics, quantitative RT-PCR, and flow cytometry was performed by using blood eosinophils from healthy subjects stimulated with IL-4, IL-5, or a combination thereof.

Results

Transcriptomic and proteomic analyses revealed that both IL-4 and IL-5 upregulate the expression of γ-gultamyl transferase 5, a fatty acid–metabolizing enzyme that converts leukotriene C₄ into leukotriene D₄. In addition, IL-4 specifically upregulates the expression of IL-1 receptor-like 1 (IL1RL1), a receptor for IL-33 and transglutaminase-2. Additional transcriptomic analysis of cells stimulated with IL-13 revealed altered gene expression profiles, characterized by the upregulation of γ-gultamyl transferase 5, transglutaminase-2, and IL1RL1. The IL-13–induced changes were not totally different from the IL-4–induced changes. Lipidomic analysis revealed that IL-5 and IL-4 additively increased the extracellular release of leukotriene D₄. In vitro experiments revealed that STAT6 and IL-4 receptor-α control the expression of these molecules in the presence of IL-4 and IL-13. Analysis of eosinophils derived from patients with allergic disorders indicated the involvement of IL-4 and IL-13 at the inflamed sites.

Conclusions

IL-4 induces the proallergic phenotype of IL1RL1^high eosinophils, with prominent cysteinyl leukotriene metabolism via STAT6. These cellular changes represent potential therapeutic targets for chronic rhinosinusitis and eosinophilic asthma.

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来源期刊

Journal of Allergy and Clinical Immunology 医学-过敏

CiteScore

25.90

自引率

7.70%

发文量

1302

审稿时长

38 days

期刊介绍： The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.