Epidermal growth factor receptor signalling regulates granulocyte-macrophage colony-stimulating factor production by airway epithelial cells and established allergic airway disease.
BACKGROUND
Airway epithelial cells (AEC) are increasingly recognized as a major signalling centre in the pathogenesis of allergic asthma. A previous study demonstrated that epithelial growth factor receptor (EGFR) signalling in AEC regulated key features of allergic airway disease. However, it is unclear what mediators are regulated by EGFR signalling in AEC, although the production of the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is EGFR dependent in keratinocytes.


OBJECTIVE
To determine whether EGFR signalling regulates GM-CSF production by human AEC downstream of the clinically relevant mediators house dust mite (HDM) and interleukin (IL)-17A and in a mouse model of established allergic asthma.


METHODS
EGFR inhibitors were used to determine whether EGFR signalling regulates GM-CSF production by cultured human AEC in response to HDM and IL-17A. The roles of EGFR ligands, p38 mitogen-activated protein kinase (MAPK) and tumour necrosis factor-alpha (TNF-α) converting enzyme (TACE) were also assessed. To determine whether EGFR regulates GM-CSF as well as key asthma characteristics in vivo, mice were chronically exposed to HDM to establish allergic airway disease and then treated with the EGFR inhibitor Erlotinib.


RESULTS
EGFR inhibition reduced HDM and IL-17A induced GM-CSF production in a dose-dependent manner in cultured human AEC. GM-CSF production also required amphiregulin, p38 MAPK signalling and protease/TACE activity. In mice with established allergic airway disease, EGFR inhibition reduced levels of GM-CSF and TNF-α, as well as airway hyperreactivity, cellular inflammation, smooth muscle thickening and goblet cell metaplasia without changes in IgE and Th1, Th2 and Th17 cytokines.


CONCLUSIONS
Results link HDM, IL-17A, amphiregulin, EGFR and GM-CSF in a mechanistic pathway in AEC and demonstrate that EGFR regulates GM-CSF production and the severity of established disease in a clinically relevant asthma model. These results identify the EGFR→GM-CSF axis as a target for therapeutic development.
Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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Acciani
Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Translational Pulmonary Science Center, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
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Suzuki
Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Translational Pulmonary Science Center, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Division of Pulmonary Medicine, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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Trapnell
Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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Le Cras
D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000276:immunology* / Q000378:metabolism; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology; D051379:Mice; D039981:Pyroglyphidae / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
D020381:Interleukin-17; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D066246:ErbB Receptors
EGFR; GM-CSF; IL-17A; chronic asthma; house dust mite