Flagellin/TLR5 responses induce mucus hypersecretion by activating EGFR via an epithelial cell signaling cascades.
Mucus hypersecretion is an important manifestation in patients with chronic inflammatory airway diseases. Excessive production of mucin leads to airway mucus obstruction and contributes to morbidity and mortality in these diseases. The molecular mechanisms underlying mucin overproduction, however, still remain largely unknown. Here, we report that the bacterium Pseudomonas aeruginosa (P. aeruginosa), an important human respiratory pathogen, induced MUC5AC mucin expression via an epithelial cell signaling cascade in human airway epithelial cells. The flagellin purified from P. aeruginosa up-regulated MUC5AC expression by activating its receptor Toll-like receptor 5 (TLR5) in 16HBE cells. This effect was inhibited by NADPH oxidase inhibitor (DPI), small interfering RNA of dual oxidase 2 (Duox2) and reactive oxygen species (ROS) scavengers (nPG and DMSO). Flagellin induced TGF-α release, and stimulated phosphorylated epidermal growth factor receptor (EGFR) and MUC5AC overproduction. These effects were prevented by EGFR and TGF-α neutralizing antibodies, metalloprotease inhibitors (GM6001 and TNF-α protease inhibitor-1) and specific knockdown of TNF-α-converting enzyme (TACE) with TACE siRNA. These findings may bring new insights into the molecular pathogenesis of P. aeruginosa infections and lead to novel therapeutic intervention for mucin overproduction in patients with P. aeruginosa infections.
Department of Geriatrics Medicine, First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Hongmei
H
Yu
Xiangdong
X
Zhou
Sha
S
Wen
Qian
Q
Xiao
D000074623:Dual Oxidases; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005408:Flagellin / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D018613:Microscopy, Confocal; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D009093:Mucus / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000378:metabolism / Q000472:pathogenicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
D055271:Mucin 5AC; D017382:Reactive Oxygen Species; D051198:Toll-Like Receptor 5; D005408:Flagellin; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431515:DUOX2 protein, human; D066246:ErbB Receptors