喘息などのアレルギー疾患が悪化するメカニズムを解明～脂肪分解経路を標的とした新たなアレルギー治療薬の開発に向けて～

2025-10-25 千葉大学

図:脂肪分解経路が病原性Th2細胞を誘導する

<関連情報>

• https://www.chiba-u.ac.jp/news/research-collab/251025_th2.html
• https://www.chiba-u.ac.jp/news/files/pdf/1025_th2.pdf
• https://www.science.org/doi/10.1126/sciimmunol.adp0849

脂肪トリグリセリドリパーゼによって制御される脂肪分解-ミクロリポファジーカスケードは病原性適応型2免疫を駆動する Lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase drives pathogenic adaptive type 2 immunity

Hiroyuki Yagyu, Masahiro Kiuchi, Atsushi Sasaki, Eisuke Itakura, […] , and Kiyoshi Hirahara
Science Immunology  Published:24 Oct 2025
DOI:https://doi.org/10.1126/sciimmunol.adp0849

Editor’s summary

Memory T helper 2 (T_H2) cells expressing high levels of the interleukin-33 (IL-33) receptor ST2 play an important role in chronic allergic inflammatory diseases. Yagyu et al. report using a mouse model of chronic allergic airway inflammation that activated T_H2 cells store long-chain unsaturated fatty acids (LC-UFAs) prevalent in inflamed lungs within lipid droplets (LDs). T_H2 cells then catabolize these LDs via adipose triglyceride lipase (ATGL)–mediated lipolysis followed by microlipophagy. LD catabolism in these cells triggers peroxisome proliferator–activated receptor γ (PPARγ), which binds the Il1rl1 locus encoding ST2 and drives the ST2^hi T_H2 cell phenotype. Patients with eosinophilic chronic rhinosinusitis have memory-type CD4 T cells in their nasal polyps with a similar microlipophagy phenotype. This pathway may, therefore, be an actionable target for treating chronic allergic diseases. —Seth Thomas Scanlon

Abstract

A unique subpopulation of memory T helper 2 (T_H2) cells expressing the interleukin-33 (IL-33) receptor ST2 drives allergic disease pathogenesis. However, the immunometabolic mechanisms that induce ST2^hi memory T_H2 cells remain unclear. We show using a mouse model of chronic allergic airway inflammation that long-chain unsaturated fatty acids (LC-UFAs) accumulate in the inflammatory milieu during chronic airway inflammation. Activated T_H2 cells take up LC-UFAs, transiently store them in lipid droplets (LDs), and catabolize LDs through lipolysis and microlipophagy. LD catabolism regulated by adipose triglyceride lipase (ATGL) activates peroxisome proliferator–activated receptor γ (PPARγ). PPARγ then binds the Il1rl1 locus encoding ST2 and induces ST2^hi effector and memory T_H2 cells. In eosinophilic chronic rhinosinusitis, CD45RO⁺ CD4 T cells in nasal polyps exhibit microlipophagy and an accessible IL1RL1 enhancer, indicating that these mechanisms are conserved in humans. Thus, the storage and catabolism of inflammatory milieu–derived LC-UFAs direct pathogenic adaptive type 2 immunity, offering potential therapeutic strategies for persistent allergic inflammation.