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31. Mycoplasma pneumoniaeModulates STAT3-STAT6/EGFR-FOXA2 Signaling To Induce Overexpression of Airway Mucins

Author

Hao, Yonghua, Kuang, Zhizhou, Jing, Jia, Miao, Jinfeng, Mei, Li Yu, Lee, Ryan J., Kim, Susie, Choe, Shawn, Krause, Duncan C., and Lau, Gee W.

Abstract

ABSTRACTAberrant mucin secretion and accumulation in the airway lumen are clinical hallmarks associated with various lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Mycoplasma pneumoniae, long appreciated as one of the triggers of acute exacerbations of chronic pulmonary diseases, has recently been reported to promote excessive mucus secretion. However, the mechanism of mucin overproduction induced by M. pneumoniaeremains unclear. This study aimed to determine the mechanism by which M. pneumoniaeinduces mucus hypersecretion by using M. pneumoniaeinfection of mouse lungs, human primary bronchial epithelial (NHBE) cells cultured at the air-liquid interface, and the conventionally cultured airway epithelial NCI-H292 cell line. We demonstrated that M. pneumoniaeinduced the expression of mucins MUC5AC and MUC5B by activating the STAT6-STAT3 and epidermal growth factor receptor (EGFR) signal pathways, which in turn downregulated FOXA2, a transcriptional repressor of mucin biosynthesis. The upstream stimuli of these pathways, including interleukin-4 (IL-4), IL-6, and IL-13, increased dramatically upon exposure to M. pneumoniae. Inhibition of the STAT6, STAT3, and EGFR signaling pathways significantly restored the expression of FOXA2 and attenuated the expression of airway mucins MUC5AC and MUC5B. Collectively, these studies demonstrated that M. pneumoniaeinduces airway mucus hypersecretion by modulating the STAT/EGFR-FOXA2 signaling pathways.

Published
2014
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32. FOXA2 depletion leads to mucus hypersecretion in canine airways with respiratory diseases.

Author

Choi, Woosuk, Yang, Alina X., Waltenburg, Michelle A., Choe, Shawn, Steiner, Madeline, Radwan, Ahmed, Lin, Jingjun, Maddox, Carrol W., Stern, Adam W., Fredrickson, Richard L., and Lau, Gee W.

Subjects
POLLUTANTS, RESPIRATORY diseases, BIOLOGICAL decontamination, ANIMAL development, CHRONIC bronchitis
Abstract

Because of exposure to environmental pollutants, infectious agents, and genetic predisposition, companion animals develop respiratory illnesses similar to those in humans. Older dogs of smaller breeds develop canine infectious respiratory disease, chronic bronchitis, and chronic obstructive pulmonary disease, with chronic lung infection, airway goblet cell hyperplasia and metaplasia, and mucus hypersecretion. Excessive mucus clogs airways, reduces gas exchanges, disables the mucociliary clearance, and reduces drug penetration. The Forkhead box protein A2 (FOXA2) is a key transcriptional regulator that maintains airway mucus homeostasis. Prior studies have shown that FOXA2 expression is frequently depleted in diseased human airways. Unfortunately, FOXA2 depletion has not been examined in dogs. Our current study indicated that both single bacterial infection by Pseudomonas aeruginosa and Bordetella bronchiseptica and polymicrobial infection by viral/bacterial pathogens depleted FOXA2 in canine airways, resulting in goblet cell hyperplasia and metaplasia and excessive mucus production. Furthermore, P. aeruginosa virulence factor pyocyanin activated the antagonistic STAT6 and epidermal growth factor receptor signalling pathways to inhibit FOXA2. Unravelling the mechanism of FOXA2 inactivation will hasten the development of non‐antibiotic therapeutics to improve mucociliary clearance of pathogens in canine airway. [ABSTRACT FROM AUTHOR]

Published
2019
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33. Pseudomonas aeruginosa pyocyanin modulates mucin glycosylation with sialyl-Lewis(x) to increase binding to airway epithelial cells.

Author

Jeffries JL, Jia J, Choi W, Choe S, Miao J, Xu Y, Powell R, Lin J, Kuang Z, Gaskins HR, and Lau GW

Subjects
Animals, Bacterial Adhesion, Cell Line, Tumor, Cystic Fibrosis microbiology, Glycosylation, Humans, Mice, Mice, Inbred C57BL, Respiratory Mucosa pathology, Sialyl Lewis X Antigen, Sialyltransferases metabolism, Tumor Necrosis Factor-alpha metabolism, Type C Phospholipases metabolism, beta-Galactoside alpha-2,3-Sialyltransferase, Cystic Fibrosis immunology, Mucins metabolism, Oligosaccharides metabolism, Pseudomonas Infections immunology, Pseudomonas aeruginosa immunology, Pyocyanine metabolism, Respiratory Mucosa metabolism
Abstract

Cystic fibrosis (CF) patients battle life-long pulmonary infections with the respiratory pathogen Pseudomonas aeruginosa (PA). An overabundance of mucus in CF airways provides a favorable niche for PA growth. When compared with that of non-CF individuals, mucus of CF airways is enriched in sialyl-Lewis(x), a preferred binding receptor for PA. Notably, the levels of sialyl-Lewis(x) directly correlate with infection severity in CF patients. However, the mechanism by which PA causes increased sialylation remains uncharacterized. In this study, we examined the ability of PA virulence factors to modulate sialyl-Lewis(x) modification in airway mucins. We found pyocyanin (PCN) to be a potent inducer of sialyl-Lewis(x) in both mouse airways and in primary and immortalized CF and non-CF human airway epithelial cells. PCN increased the expression of C2/4GnT and ST3Gal-IV, two of the glycosyltransferases responsible for the stepwise biosynthesis of sialyl-Lewis(x), through a tumor necrosis factor (TNF)-α-mediated phosphoinositol-specific phospholipase C (PI-PLC)-dependent pathway. Furthermore, PA bound more efficiently to airway epithelial cells pre-exposed to PCN in a flagellar cap-dependent manner. Importantly, antibodies against sialyl-Lewis(x) and anti-TNF-α attenuated PA binding. These results indicate that PA secretes PCN to induce a favorable environment for chronic colonization of CF lungs by increasing the glycosylation of airway mucins with sialyl-Lewis(x).

Published
2016
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