IL-27 disturbs lipid metabolism and restrains mitochondrial activity to inhibit γδ T17 cell-mediated skin inflammation

  • Cell Death Dis. 2024 Jul 9;15(7):491. doi: 10.1038/s41419-024-06887-0.
Mingyue Zhang  #  1  2  3 ,  Dehai Li  #  4 ,  Jing Zhu  #  2 ,  Xue Xia  1  2  3 ,  Hua Zhang  5 ,  Jie Wu  2 ,  Shengli Wang  1  2  3 ,  Anyi Deng  1  2  3 ,  Qiong Wen  1  2  3 ,  Jingyi Tan  1  2  3 ,  Jianlei Hao  1  2  3 ,  Jun Jiang  1 ,  Xiucong Bao  6 ,  Guodong Sun  7 ,  Jiajing Lu  8  9 ,  Quanli Yang  1  2 ,  Hengwen Yang  10  11  12 ,  Guangchao Cao  13  14  15 ,  Zhinan Yin  16  17  18 ,  Qian Wang  19  20  21
Affiliations
  • 1. Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai, 519000, China.
  • 2. State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, China.
  • 3. Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China.
  • 4. Tianjian Laboratory of Advanced Biomedical Sciences, Institute of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 5. Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China.
  • 6. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 7. Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, 517000, China.
  • 8. Department of Dermatology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, China.
  • 9. Institute of Psoriasis, School of Medicine, Tongji University, Shanghai, 200443, China.
  • 10. Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai, 519000, China. [email protected].
  • 11. State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, China. [email protected].
  • 12. Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China. [email protected].
  • 13. Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai, 519000, China. [email protected].
  • 14. State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, China. [email protected].
  • 15. Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China. [email protected].
  • 16. Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai, 519000, China. [email protected].
  • 17. State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, China. [email protected].
  • 18. Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China. [email protected].
  • 19. Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai, 519000, China. [email protected].
  • 20. State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, China. [email protected].
  • 21. Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China. [email protected].
  • # Contributed equally.
PMID: 38982043 DOI: 10.1038/s41419-024-06887-0
Abstract

IL-17+ γδ T cells (γδ T17) are kick-starters of inflammation due to their strict immunosurveillance of xenobiotics or cellular damages and rapid response to pro-inflammatory stimulators. IL-27 is a well-recognized pleiotropic immune regulator with potent inhibitory effects on type 17 immune responses. However, its actions on γδ T17 mediated inflammation and the underlying mechanisms are less well understood. Here we find that IL-27 inhibits the production of IL-17 from γδ T cells. Mechanistically, IL-27 promotes lipolysis while inhibits lipogenesis, thus reduces the accumulation of lipids and subsequent membrane Phospholipids, which leads to mitochondrial deactivation and ensuing reduction of IL-17. More importantly, IL27RA deficient γδ T cells are more pathogenic in an imiquimod-induced murine psoriasis model, while intracutaneous injection of rmIL-27 ameliorates psoriatic inflammation. In summary, this work uncovered the metabolic basis for the immune regulatory activity of IL-27 in restraining γδ T17 mediated inflammation, which provides novel insights into IL-27/IL-27Ra signaling, γδ T17 biology and the pathogenesis of psoriasis.

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