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

Nat Commun. 2023 Dec 22;14(1):8525. 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.

MeSH terms

  • Airway Remodeling
  • Animals
  • Asthma* / metabolism
  • Disease Models, Animal
  • Humans
  • Inflammation
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism
  • Mice
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Sirtuins* / genetics
  • Virulence


  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Sirtuins
  • SIRT6 protein, human
  • Sirt6 protein, mouse