Lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase drives pathogenic adaptive type 2 immunity
A unique subpopulation of memory T helper 2 (T<sub>H</sub>2) cells expressing the interleukin-33 (IL-33) receptor ST2 drives allergic disease pathogenesis. However, the immunometabolic mechanisms that induce ST2<sup>hi</sup> memory T<sub>H</sub>2 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<sub>H</sub>2 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 <i>Il1rl1</i> locus encoding ST2 and induces ST2<sup>hi</sup> effector and memory T<sub>H</sub>2 cells. In eosinophilic chronic rhinosinusitis, CD45RO<sup>+</sup> CD4 T cells in nasal polyps exhibit microlipophagy and an accessible <i>IL1RL1</i> 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.
Authors
- Toyoyuki Hanazawa (ORCID: https://orcid.org/0000-0001-9721-5662)
- Eisuke Itakura (ORCID: https://orcid.org/0000-0001-7248-9333)
- Kota Kokubo (ORCID: https://orcid.org/0000-0001-6896-1981)
- Takahiro Arano
- Masahiro Kiuchi (ORCID: https://orcid.org/0000-0002-0227-4502)
- Kaori Tsuji (ORCID: https://orcid.org/0009-0000-6270-7106)
- Syuji Yonekura (ORCID: https://orcid.org/0000-0002-1408-9072)
- Kiyoshi Hirahara (ORCID: https://orcid.org/0000-0002-9128-9449)
- Yuri Sonobe
- Shinichiro Motohashi (ORCID: https://orcid.org/0000-0002-9332-3129)
- Takeshi Kaneko (ORCID: https://orcid.org/0000-0001-9292-307X)
- Damon J. Tumes (ORCID: https://orcid.org/0000-0001-5709-857X)
- Takahisa Hishiya (ORCID: https://orcid.org/0000-0001-7049-8615)
- K. Ohishi (ORCID: https://orcid.org/0009-0003-6194-2632)
- Tomohisa Iinuma (ORCID: https://orcid.org/0000-0002-9940-5520)
- Atsushi Onodera (ORCID: https://orcid.org/0000-0002-3715-9408)
- Yu Hara (ORCID: https://orcid.org/0000-0002-2574-2516)
- Ami Aoki (ORCID: https://orcid.org/0000-0002-8785-5612)
- Hiroyuki Yagyu (ORCID: https://orcid.org/0000-0003-4336-9919)
- Junya Kurita (ORCID: https://orcid.org/0000-0003-3526-4893)
- Rie Shinmi (ORCID: https://orcid.org/0009-0000-9831-8399)
- Motoko Y. Kimura (ORCID: https://orcid.org/0000-0002-5607-5066)
- Atsushi Sasaki (ORCID: https://orcid.org/0000-0001-6127-7714)
- Toshinori Nakayama (ORCID: https://orcid.org/0000-0002-1434-2007)
- Takuto Hiramoto
- S.S. Baba
- Chiaki Iwamura (ORCID: https://orcid.org/0000-0003-3537-8073)
Institutions
- South Australia Pathology (AU)
- Chiba University (JP)
- University of South Australia (AU)
- Japan Agency for Medical Research and Development (JP)
- Niigata University Medical and Dental Hospital (JP)
- Synergy Health (US)
- Centre for Cancer Biology (AU)
- The University of Adelaide (AU)
- Niigata University (JP)
- Yokohama City University (JP)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-10-24
- DOI
- https://doi.org/10.1126/sciimmunol.adp0849
- Citations
- 1
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.80