Dysregulation of IL-17A is strongly associated with airway inflammation and remodeling in severe asthma. However, the molecular mechanisms that regulate IL-17A remain unclear.
On December 22, 2023, Tianwen Lai, Jing Tang and Xiao Gao from Guangdong Medical University jointly published a study titled "Epithelial Sirt6 Governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling" in Nature Communications** In this study, epithelial sirtuin 6 (SIRT6) was used as an epigenetic regulator to control the pathogenicity of IL-17A in severe asthma. SIRT6-specific knockout mice can combat allergen-induced airway inflammation and remodeling by inhibiting IL-17A-mediated inflammatory chemokine and mesenchymal reprogramming.
Mechanistically, SIRT6 directly interacts with ROR T and mediates the deacetylation of ROR T at position 192 through its PPXY motif. SIRT6 promotes the recruitment of ROR T to the IL-17A gene promoter and enhances its transcription. In patients with severe asthma, high expression of SIRT6 was positively correlated with airway remodeling and disease severity. SIRT6 inhibitor (OSS 128167) significantly reduced airway inflammation and remodeling in mice. In summary, these results revealed the pathogenic function of SIRT6 in regulating IL-17A in severe asthma, suggesting that SIRT6 may become a potential target for severe asthma.
Asthma is a chronic inflammatory disease of the airways that affects 300 million patients worldwide, of which patients with severe asthma account for <10%, but account for the lion's share of clinical costs and mortality. Chronic airway inflammation and airway remodeling, which refers to structural changes in the bronchi, are key pathological features of severe asthma. The degree of airway remodeling is strongly correlated with decreased lung function and steroid resistance. However, the mechanisms underlying airway inflammation and remodeling processes in severe asthma are not fully understood. Patients with severe asthma have eosinophilic inflammation or neutrophilic inflammation or mixed myelocytic (eosinophilic and neutrophilic inflammation). Common indoor and outdoor environmental exposures can affect airway inflammation in asthma. Airway epithelial cells are the first site of exposure to environmental factors, leading to the development of chronic inflammation and ultimately airway remodeling. HDM is a complex mixture of mite allergens and microbial products. LPS is an endotoxin that is highly affected by gram-negative membranes and environmental contamination, and the level of LPS is related to the severity of asthma and decreased lung function. The pathological process includes a combination of increased epithelial-mesenchymal transition (EMT), myofibroblast transformation, and extracellular matrix (ECM) deposition. Recent studies have shown that interleukin (IL) 17A plays a key role in the EMT process and contributes to severe asthma. Unlike other asthma phenotypes, the IL-17A-associated neutrophilic asthma (NA) phenotype exhibits frequent asthma exacerbations or more severe asthma. IL-17A promotes airway goblet cell proliferation, mucus hypersecretion, and fibrosis, thereby promoting airway remodeling. However, how this cytokine promotes airway inflammation and remodeling, and accelerates disease progression in severe asthma remains unclear. Acetylation is a widely occurring epigenetic modification of proteins that is involved in a variety of biological processes. The acetylation state is maintained by a complex equilibrium of histone deacetylase (HDAC) and histone acetyltransferase (HAT). In recent years, the physiological function of the sirtuin deacetylase family (SIRT1-SIRT7) has been studied. Among the 7 sirtuins, SIRT6 plays a leading role in regulating cell proliferation, stress response, genome stabilization, energy balance, and aging. However, whether and how SIRT6 regulates the pathogenicity of IL-17A in severe asthma has not been deciphered.
SIRT6 inhibitor OSS 128167 prevents airway remodeling in asthma mice (Image courtesy of Nature Communications) Using a variety of human samples (e.g., airway biopsy samples, bronchoalveolar lavage fluid [BALF], peripheral blood) and different mouse models of severe asthma, the study identified epithelial SIRT6 as an important epigenetic regulator of IL-17A secretion during the progression of severe asthma. Absence or inhibition of SIRT6 results in impaired IL-17A secretion in airway epithelial cells and ameliorates airway remodeling in severe asthma through ROR T-K192 deacetylation. Taken together, these data support the hypothesis that blocking SIRT6 can prevent IL-17A-mediated airway inflammation and remodeling in severe asthma. Reference message: