title: Mycoplasma pneumoniae modulates STAT3-STAT6/EGFR-FOXA2 signaling to induce overexpression of airway mucins.
abstract: Aberrant 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. pneumoniae remains unclear. This study aimed to determine the mechanism by which M. pneumoniae induces mucus hypersecretion by using M. pneumoniae infection 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. pneumoniae induced 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. pneumoniae induces airway mucus hypersecretion by modulating the STAT/EGFR-FOXA2 signaling pathways.
authors.affiliation: Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Zhizhou
authors.initials: Z
authors.lastname: Kuang
authors.affiliation: Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Jing
authors.affiliation: College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, People's Republic of China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Miao
authors.affiliation: Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Li Yu
authors.initials: LY
authors.lastname: Mei
authors.affiliation: Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Susie
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Choe
authors.affiliation: Department of Microbiology, University of Georgia, Athens, Georgia, USA.
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Krause
authors.affiliation: Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA geelau@illinois.edu.
authors.forename: Gee W
authors.initials: GW
authors.lastname: Lau
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D066246:ErbB Receptors / Q000378:metabolism; D020869:Gene Expression Profiling; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D008810:Mice, Inbred C57BL; D055271:Mucin 5AC / Q000378:metabolism; D055257:Mucin-5B / Q000378:metabolism; D009077:Mucins / Q000378:metabolism*; D009177:Mycoplasma pneumoniae / Q000502:physiology*; D011019:Pneumonia, Mycoplasma / Q000382:microbiology / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C496502:FOXA2 protein, human; C496503:Foxa2 protein, mouse; C524678:MUC5AC protein, human; C524578:MUC5B protein, human; D055271:Mucin 5AC; D055257:Mucin-5B; D009077:Mucins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494087:Stat3 protein, mouse; C494100:Stat6 protein, mouse; D051542:Hepatocyte Nuclear Factor 3-beta; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors