Overexpression of sirtuin 6 suppresses allergic airway inflammation through deacetylation of GATA3.

Abstract Sirtuin 6, an NAD+-dependent deacetylase and mono-ADP-ribosyl transferase, is known to have an anti-inflammatory function. It is unclear, however, whether sirtuin 6 also negatively contributes to the development of allergic airway inflammation (AAI). To elucidate the role of sirtuin 6 in AAI pathogenesis and its underlying mechanism. An adenovirus expressing Sirt6 (AdSirt6) and a catalytically inactive Sirt6-H133Y were used to deliver sirtuin 6. We analyzed the features of AAI in BALB/c mice after sensitization with two different allergens, ovalbumin (OVA) and house dust mite (HDM). Sirtuin 6 level increased in lung tissues of OVA-challenged mice. AdSirt6 injection before allergen challenge reduced all cardinal features of AAI; eosinophilic airway inflammation, mucus hypersecretion, airway hyperresponsiveness, and Th2 immune responses were markedly suppressed. Furthermore, the differentiation of CD4+ T cells into Th2 cells was also decreased in the draining lymph nodes of AdSirt6-injected mice. Finally, in vitro overexpression studies and asthmatic lung tissues demonstrated that sirtuin 6 interacts and deacetylates GATA3, a master transcriptional regulator of Th2 immune responses. Our results showed that local overexpression of sirtuin 6 was effective in preventing AAI through the deacetylation of GATA3.