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

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 Zheng, Yiming Shao, Haitao Lin, Xiao Gao (), Jing Tang () and Tianwen Lai ()
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Jingyun Quan: 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

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-44179-x

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