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

• Published in: Nature communications Vol. 14; no. 1; pp. 8525 - 14
• Main Authors: Quan, Jingyun, Wen, Xiaoxia, Su, Guomei, Zhong, Yu, Huang, Tong, Xiong, Zhilin, Huang, Jiewen, Lv, Yingying, Li, Shihai, Luo, Shuhua, Luo, Chaole, Cai, Xin, Lai, Xianwen, Xiang, Yuanyuan, Zheng, Song Guo, Shao, Yiming, Lin, Haitao, Gao, Xiao, Tang, Jing, Lai, Tianwen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.12.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/127/1213; 631/250/262; 631/250/347; 631/80/304; 692/699/1785/31; Airway Remodeling; Animal models; Animals; Asthma; Asthma - metabolism; Chemokines; Clonal deletion; Deacetylation; Disease Models, Animal; Epigenetics; Epithelial cells; Epithelium; Humanities and Social Sciences; Humans; Inflammation; Interleukin-17 - genetics; Interleukin-17 - metabolism; Lungs; Lysine; Mice; Molecular modelling; multidisciplinary; Nuclear Receptor Subfamily 1, Group F, Member 3; Pathogenicity; Pathogens; Respiratory tract diseases; Science; Science (multidisciplinary); Sirtuins - genetics; Therapeutic targets; Virulence
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44179-x

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. IL-17 mediated inflammation in the lung is mediated by different effector molecules. Here the authors show that the epigenetic regulator epithelial sirtuin 6 (Sirt6) is associated with lung inflammation in asthma patients and that Sirt6 contributes to promotion of inflammation in mouse asthma models.