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Epithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling

Author

Listed:
  • Jingyun Quan

    (Guangdong Medical University
    Affiliated Hospital of Guangdong Medical University)

  • Xiaoxia Wen

    (Affiliated Hospital of Guangdong Medical University)

  • Guomei Su

    (Affiliated Hospital of Guangdong Medical University)

  • Yu Zhong

    (Affiliated Hospital of Guangdong Medical University)

  • Tong Huang

    (Affiliated Hospital of Guangdong Medical University)

  • Zhilin Xiong

    (Affiliated Hospital of Guangdong Medical University)

  • Jiewen Huang

    (Affiliated Hospital of Guangdong Medical University)

  • Yingying Lv

    (Guangdong Medical University)

  • Shihai Li

    (Affiliated Hospital of Guangdong Medical University)

  • Shuhua Luo

    (Affiliated Hospital of Guangdong Medical University)

  • Chaole Luo

    (Guangdong Medical University)

  • Xin Cai

    (Affiliated Hospital of Guangdong Medical University)

  • Xianwen Lai

    (Affiliated Hospital of Guangdong Medical University)

  • Yuanyuan Xiang

    (Affiliated Hospital of Guangdong Medical University)

  • Song Guo Zheng

    (Guangdong Medical University)

  • Yiming Shao

    (Guangdong Medical University)

  • Haitao Lin

    (Affiliated Hospital of Guangdong Medical University)

  • Xiao Gao

    (Affiliated Hospital of Guangdong Medical University)

  • Jing Tang

    (Affiliated Hospital of Guangdong Medical University)

  • Tianwen Lai

    (Guangdong Medical University
    Affiliated Hospital of Guangdong Medical University)

Abstract

Dysregulation of IL-17A is closely associated with airway inflammation and remodeling in severe asthma. However, the molecular mechanisms by which IL-17A is regulated remain unclear. Here we identify epithelial sirtuin 6 (SIRT6) as an epigenetic regulator that governs IL-17A pathogenicity in severe asthma. Mice with airway epithelial cell-specific deletion of Sirt6 are protected against allergen-induced airway inflammation and remodeling via inhibiting IL-17A-mediated inflammatory chemokines and mesenchymal reprogramming. Mechanistically, SIRT6 directly interacts with RORγt and mediates RORγt deacetylation at lysine 192 via its PPXY motifs. SIRT6 promotes RORγt recruitment to the IL-17A gene promoter and enhances its transcription. In severe asthma patients, high expression of SIRT6 positively correlates with airway remodeling and disease severity. SIRT6 inhibitor (OSS_128167) treatment significantly attenuates airway inflammation and remodeling in mice. Collectively, these results uncover a function for SIRT6 in regulating IL-17A pathogenicity in severe asthma, implicating SIRT6 as a potential therapeutic target for severe asthma.

Suggested Citation

  • Jingyun Quan & Xiaoxia Wen & Guomei Su & Yu Zhong & Tong Huang & Zhilin Xiong & Jiewen Huang & Yingying Lv & Shihai Li & Shuhua Luo & Chaole Luo & Xin Cai & Xianwen Lai & Yuanyuan Xiang & Song Guo Zhe, 2023. "Epithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44179-x
    DOI: 10.1038/s41467-023-44179-x
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    References listed on IDEAS

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    1. Alan K. Okada & Kazuki Teranishi & Mark R. Ambroso & Jose Mario Isas & Elena Vazquez-Sarandeses & Joo-Yeun Lee & Arthur Alves Melo & Priyatama Pandey & Daniel Merken & Leona Berndt & Michael Lammers &, 2021. "Lysine acetylation regulates the interaction between proteins and membranes," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Xiaofeng Zheng & Julienne L. Carstens & Jiha Kim & Matthew Scheible & Judith Kaye & Hikaru Sugimoto & Chia-Chin Wu & Valerie S. LeBleu & Raghu Kalluri, 2015. "Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer," Nature, Nature, vol. 527(7579), pages 525-530, November.
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