Myricetin ameliorates airway inflammation and remodeling in asthma by activating Sirt1 to regulate the JNK/Smad3 pathway

Abstract

BackgroundMyricetin has various biological activities and health benefits; however, its effects on airway remodeling in asthma have not been reported. PurposeWe aimed to investigate the possibility that myricetin improves airway remodeling by activating Sirt1 and has potential as a new treatment for asthma. MethodsRAW 264.7 cells were stimulated with lipopolysaccharide and co-cultured with 3T6 cells in vitro to simulate the in vivo effects of inflammation on airway remodeling. Using an ovalbumin-induced chronic asthma mouse model, we compared changes in inflammatory factors and airway remodeling-related factors under treatment with myricetin and/or the Sirt1 inhibitor EX-527 using western blotting and quantitative PCR. Expression plasmids carrying Smad3 site mutations were transfected into 3T6 cells to identify the Sirt1 deacetylation site on Smad3 protein. ResultsMyricetin significantly reduced the infiltration of airway inflammatory cells and the production of interleukin (IL)-6 and IL-5, and inhibited mucus secretion by goblet cells, collagen fiber proliferation, and the increase in inflammatory cells in bronchoalveolar lavage fluid from asthmatic mice. Results of in vitro experiments were consistent with those conducted in vivo. Exploring the mechanism of action of myricetin, we found that myricetin downregulated the levels of phosphorylated (p)-JNK, p-Smad3, and acetylated Smad3 proteins by activating Sirt1 both in vivo and in vitro. K341 was identified as the main deacetylation site of Smad3 by myricetin-activated Sirt1. ConclusionMyricetin ameliorates airway inflammation and remodeling in asthma by activating Sirt1 to regulate the JNK/Smad3 pathway.