Exendin-4 restores airway mucus homeostasis through the GLP1R-PKA-PPARγ-FOXA2-phosphatase signaling

Mucosal Immunol. 2020 Jul;13(4):637-651. doi: 10.1038/s41385-020-0262-1. Epub 2020 Feb 7.


Goblet cell hyperplasia and metaplasia and excessive mucus are prominent pathologies of chronic airway diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and chronic bronchitis. Chronic infection by respiratory pathogens, including Pseudomonas aeruginosa, exacerbates cyclical proinflammatory responses and mucus hypersecretion. P. aeruginosa and its virulence factor pyocyanin contribute to these pathologies by inhibiting FOXA2, a key transcriptional regulator of mucus homeostasis, through activation of antagonistic signaling pathways EGFR-AKT/ERK1/2 and IL-4/IL-13-STAT6-SPDEF. However, FOXA2-targeted therapy has not been previously explored. Here, we examined the feasibility of repurposing the incretin mimetic Exendin-4 to restore FOXA2-mediated airway mucus homeostasis. We have found that Exendin-4 restored FOXA2 expression, attenuated mucin production in COPD and CF-diseased airway cells, and reduced mucin and P. aeruginosa burden in mouse lungs. Mechanistically, Exendin-4 activated the GLP1R-PKA-PPAR-γ-dependent phosphatases PTEN and PTP1B, which inhibited key kinases within both EGFR and STAT6 signaling cascades. Our results may lead to the repurposing of Exendin-4 and other incretin mimetics to restore FOXA2 function and ultimately regulate excessive mucus in diseased airways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Disease Susceptibility
  • ErbB Receptors / metabolism
  • Exenatide / pharmacology*
  • Gene Expression
  • Glucagon-Like Peptide-1 Receptor / metabolism*
  • Hepatocyte Nuclear Factor 3-beta / genetics
  • Hepatocyte Nuclear Factor 3-beta / metabolism*
  • Homeostasis*
  • Humans
  • Models, Biological
  • Mucins / genetics
  • Mucins / metabolism
  • PPAR gamma / metabolism*
  • Protein Binding
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pulmonary Disease, Chronic Obstructive / etiology
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • Pulmonary Disease, Chronic Obstructive / pathology
  • Respiratory Mucosa / drug effects*
  • STAT6 Transcription Factor / metabolism
  • Signal Transduction / drug effects*


  • FOXA2 protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Mucins
  • PPAR gamma
  • STAT6 Transcription Factor
  • Hepatocyte Nuclear Factor 3-beta
  • Exenatide
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Cyclic AMP-Dependent Protein Kinases