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. 2024 Nov;154(5):1277-1288.
doi: 10.1016/j.jaci.2024.07.012. Epub 2024 Jul 25.

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

Keeya Sunata  1 , Jun Miyata  2 , Yusuke Kawashima  3 , Ryo Konno  3 , Masaki Ishikawa  3 , Yoshinori Hasegawa  3 , Ryuta Onozato  4 , Yo Otsu  4 , Emiko Matsuyama  4 , Hisashi Sasaki  5 , Shinichi Okuzumi  4 , Takao Mochimaru  6 , Katsunori Masaki  4 , Hiroki Kabata  4 , Akihiko Kawana  5 , Makoto Arita  7 , Koichi Fukunaga  4
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Free article

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

Keeya Sunata et al. J Allergy Clin Immunol. 2024 Nov.
Free article

Abstract

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 IL1RL1high eosinophils, with prominent cysteinyl leukotriene metabolism via STAT6. These cellular changes represent potential therapeutic targets for chronic rhinosinusitis and eosinophilic asthma.

Keywords: Asthma; IL-4; IL1RL1; STAT6; chronic rhinosinusitis; eosinophil; leukotriene; omics analysis; transglutaminase-2; γ-glutamyl transferase 5.

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Conflict of interest statement

Disclosure statement Supported by the Japanese Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research Program (KAKENHI) (grants 15H05897, 15H05898, and 20H00495 [to M.A.]), Japan Science and Technology Agency program Exploratory Research for Advanced Technology (JST-ERATO) (grant JPMJER2101 [to M.A.]), Research Grant on Allergic Disease and Immunology from the Japan Agency for Medical Research and Development (grant 22ek0410097 [to J.M.]), JSPS Grant-in-Aid for Young Scientists (grant 20K17239 [to J.M.]), RIKEN Special Postdoctoral Researchers Program (to J.M.), GSK Japan Research Grant 2018 (to J.M.), and Grant-in-Aid for Research of the ONO Medical Research Foundation (to J.M.). Disclosure of potential conflict of interest: J. Miyata, K. Masaki, H. Kabata, and K. Fukunaga report receiving research grant support from GSK and AstraZeneca. J. Miyata and K. Fukunaga report receiving payments for lectures from GSK, AstraZeneca, and Sanofi. K. Masaki reports receiving payments for lectures from GSK and AstraZeneca, and GSK. H. Kabata reports receiving payments for lectures from AstraZeneca and Sanofi. The rest of the authors declare that they have no relevant conflicts of interest.