miR-181-5p attenuates neutrophilic inflammation in asthma by targeting DEK

• Published in: International immunopharmacology 2022-11, Vol.112, p.109243-109243, Article 109243
• Main Authors: Song, Yilan, Wang, Zhiguang, Jiang, Jingzhi, Piao, Yihua, Bai, Qiaoyun, Piao, Qinji, Li, Li, Xu, Chang, Liu, Hanye, Piao, Hongmei, Li, Liangchang, Yan, Guanghai
• Format: Article
• Language: English
• Subjects: Animals; Asthma - metabolism; beta Catenin - metabolism; Chromosomal Proteins, Non-Histone - metabolism; DEK; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Glycogen Synthase Kinase 3 beta - metabolism; Humans; Inflammation - metabolism; Interleukin-8 - metabolism; Ligands; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; miR-181b-5p; Neutrophilic asthma; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Poly-ADP-Ribose Binding Proteins - genetics; Poly-ADP-Ribose Binding Proteins - metabolism
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2022.109243

•DEK was overexpressed in neutrophilic asthma.•miR-181b-5p was decreased in neutrophilic asthma.•miR-181b-5p attenuate neutrophilic asthma through DEK/p-GSK-3βSer9/β-catenin/MMP-9 and DEK/Wnt/DRP1/MMP-9 axis. We investigated the regulatory role of miR-181b-5p in neutrophilic asthma and its mechanisms by targeting DEK. DEK, matrix metalloproteinase (MMP)-2, and MMP-9 were overexpressed and the miR-181b-5p was decreased in mice with neutrophilic asthma. DEK was a direct target of miR-181b-5p. In mouse model, miR-181b-5p agomir had an inhibitory effect on airway inflammation and remodeling. miR-181b-5p inhibited DEK/p-GSK-3βSer9/β-catenin/MMP-9 pathway activation by regulating Wnt ligands in BEAS-2B and 16HBE cells. The ability of supernatants from human bronchial epithelial cells (hBECs) co-stimulated with CXCL8 (IL-8) and miR-181b-5p to induce NETs was weaker than that of IL-8 alone. Moreover, DEK overexpression led to excessive mitochondrial dysfunction, including DRP1 up-regulation, p-DRP1ser637 and MFN2 down-regulation, mitochondrial membrane potential loss, excessive mtROS generation and mitochondrial incompleteness. Interestingly, all these phenotypes were rescued by Wnt inhibitor DKK-1 and miR-181b-5p agomir. Additionally, inhibition of DRP1 with Mdivi-1 decreased MMP-9 on BEAS-2B cells. Overall, miR-181b-5p could attenuate neutrophilic asthma through inhibition of NETs release, DEK/p-GSK-3βSer9/β-catenin/MMP-9 pathway, DEK/Wnt/DRP1/MMP-9 and mitochondria damage. It may become a new therapeutic target for neutrophilic asthma.