Epidermal growth factor receptor signaling regulates granulocyte-macrophage colony-stimulating factor production by airway epithelial cells and established allergic airway disease

Abstract

Background

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

Objectives

To determine if EGFR signaling 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 signaling 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 tumor necrosis factor alpha (TNFα) converting enzyme (TACE) were also assessed. To determine if 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 signaling, and protease/TACE activity. In mice with established allergic airway disease, EGFR inhibition reduced levels of GM-CSF and TNFα, 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 and Clinical Relevance

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.