Targeted inhibition of GATA-6 attenuates airway inflammation and remodeling by regulating caveolin-1 through TLR2/MyD88/NF-κB in murine model of asthma.
The purpose of this study was to evaluate the effects of GATA-6 on airway inflammation and remodeling and the underlying mechanisms in a murine model of chronic asthma. Female BALB/c mice were randomly divided into four groups: phosphate-buffered saline control (PBS), ovalbumin (OVA)-induced asthma group (OVA), OVA+ siNC and OVA+ siGATA-6. In this mice model, GATA-6 expression level was significantly elevated and the expression in Caveolin-1 (Cav-1) inversely correlated with the abundance of GATA-6 in OVA-induced asthma of mice. Silencing of GATA-6 gene expression upregulated Cav-1 expression. Additionally, downregulation of GATA-6 dramatically decreased OVA-challenged inflammation, infiltration, and mucus production. Moreover, silencing of GATA-6 resulted in decreased levels of immunoglobulin E (IgE) and inflammatory mediators and reduced inflammatory cell accumulation, as well as inhibiting the expression of important mediators including matrix metalloproteinase (MMP)-2 and MMP-9, TGF-β1, and a disintegrin and metalloproteinase 8 (ADAM8) and ADAM33, which is related to airway remodeling. Further analysis confirmed that silencing of GATA-6 attenuated OVA-induced airway inflammation and remodeling through the TLR2/MyD88 and NF-κB pathway. In conclusion, these findings indicated that the downregulation of GATA-6 effectively inhibited airway inflammation and reversed airway remodeling via Cav-1, at least in part through downregulation of TLR2/MyD88/NF-κB, which suggests that GATA-6 represents a promising therapeutic strategy for human allergic asthma.
Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China. Electronic address: pingfangsx@163.com.
Ping
P
Fang
Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China.
Hong-Yang
HY
Shi
Key Laboratory, Biochemical Information Engineering of Ministry of Education Xi'an Jiaotong University School of Life Science and Technology, Xi'an 710049, Shaanxi, PR China.
Xiao-Ming
XM
Wu
Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China.
Yong-Hong
YH
Zhang
Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China.
Yu-Jie
YJ
Zhong
Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China.
Wen-Jing
WJ
Deng
Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China.
Yu-Ping
YP
Zhang
Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China.
Mei
M
Xie
D056151:Airway Remodeling / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D051242:Caveolin 1 / Q000096:biosynthesis* / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D050993:GATA6 Transcription Factor / Q000096:biosynthesis* / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D055785:Gene Knockdown Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism
D051242:Caveolin 1; D050993:GATA6 Transcription Factor; C494760:Gata6 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2
Airway inflammation; Airway remodeling; Asthma; Caveolin-1 (Cav-1); GATA-6