| Title : Lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase drives pathogenic adaptive type 2 immunity - Yagyu_2025_Sci.Immunol_10_eadp0849 |
| Author(s) : Yagyu H , Kiuchi M , Sasaki A , Itakura E , Kokubo K , Iwamura C , Onodera A , Aoki A , Hishiya T , Tsuji K , Hiramoto T , Shinmi R , Sonobe Y , Arano T , Ohishi K , Baba S , Kurita J , Iinuma T , Yonekura S , Hara Y , Kimura MY , Motohashi S , Tumes DJ , Hanazawa T , Kaneko T , Nakayama T , Hirahara K |
| Ref : Sci Immunol , 10 :eadp0849 , 2025 |
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Abstract :
A unique subpopulation of memory T helper 2 (T(H)2) cells expressing the interleukin-33 (IL-33) receptor ST2 drives allergic disease pathogenesis. However, the immunometabolic mechanisms that induce ST2(hi) memory T(H)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(H)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 gamma (PPARgamma). PPARgamma then binds the Il1rl1 locus encoding ST2 and induces ST2(hi) effector and memory T(H)2 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. |
| PubMedSearch : Yagyu_2025_Sci.Immunol_10_eadp0849 |
| PubMedID: 41134875 |
Yagyu H, Kiuchi M, Sasaki A, Itakura E, Kokubo K, Iwamura C, Onodera A, Aoki A, Hishiya T, Tsuji K, Hiramoto T, Shinmi R, Sonobe Y, Arano T, Ohishi K, Baba S, Kurita J, Iinuma T, Yonekura S, Hara Y, Kimura MY, Motohashi S, Tumes DJ, Hanazawa T, Kaneko T, Nakayama T, Hirahara K (2025)
Lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase drives pathogenic adaptive type 2 immunity
Sci Immunol
10 :eadp0849
Yagyu H, Kiuchi M, Sasaki A, Itakura E, Kokubo K, Iwamura C, Onodera A, Aoki A, Hishiya T, Tsuji K, Hiramoto T, Shinmi R, Sonobe Y, Arano T, Ohishi K, Baba S, Kurita J, Iinuma T, Yonekura S, Hara Y, Kimura MY, Motohashi S, Tumes DJ, Hanazawa T, Kaneko T, Nakayama T, Hirahara K (2025)
Sci Immunol
10 :eadp0849