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

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

doi:10.1016/j.jaci.2024.07.012

Multiomics analysis identified IL-4-induced IL1RL1^high eosinophils characterized by prominent cysteinyl leukotriene metabolism

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

Authors

Keeya Sunata¹, Jun Miyata², Yusuke Kawashima³, Ryo Konno³, Masaki Ishikawa³, Yoshinori Hasegawa³, Ryuta Onozato⁴, Yo Otsu⁴, Emiko Matsuyama⁴, Hisashi Sasaki⁵, Shinichi Okuzumi⁴, Takao Mochimaru⁶, Katsunori Masaki⁴, Hiroki Kabata⁴, Akihiko Kawana⁵, Makoto Arita⁷, Koichi Fukunaga⁴

Affiliations

¹ Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan; Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
² Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan; Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan; Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Saitama, Japan. Electronic address: junmiyata.a2@keio.jp.
³ Department of Applied Genomics, Kazusa DNA Research Institute, Chiba, Japan.
⁴ Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
⁵ Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
⁶ Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan; Department of Respiratory Medicine, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
⁷ Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan; Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan; Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan; Human Biology-Microbiome-Quantum Research Center (WPI-Bio2Q), Keio University, Tokyo, Japan.

PMID: 39067484
DOI: 10.1016/j.jaci.2024.07.012

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 IL1RL1^high 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.

MeSH terms

Adult
Eosinophils* / immunology
Eosinophils* / metabolism
Humans
Interleukin-1 Receptor-Like 1 Protein* / genetics
Interleukin-1 Receptor-Like 1 Protein* / metabolism
Interleukin-4* / metabolism
Interleukin-4* / pharmacology
Leukotrienes / metabolism
Male
Multiomics
Proteomics
Transcriptome

Substances

Interleukin-4
Interleukin-1 Receptor-Like 1 Protein
IL1RL1 protein, human
Leukotrienes
IL4 protein, human