Autocrine effect of EGFR ligands on the pro-inflammatory response induced by PM2.5 exposure in human bronchial epithelial cells

Abstract

Human exposure to PM(2.5) (particulate matter with an aerodynamic diameter below 2.5 μm) is known to be responsible for airway inflammation and may also induce airway remodelling. In respiratory epithelial cells exposed to PM(2.5), releases of pro-inflammatory cytokines such as granulocyte macrophage-colony stimulating factor (GM-CSF) and growth factor ligands of the epidermal growth factor receptor (EGFR) are increased. The present study aimed at determining the involvement of EGFR ligands by autocrine effects in PM(2.5)-induced GM-CSF release. PM(2.5) exposure triggers GM-CSF release by human bronchial epithelial (HBE) cells. This release is dependent on EGFR activation by ligand binding as it is inhibited by AG1478, an inhibitor of EGFR tyrosine kinase activity as well as by a neutralizing anti-EGFR antibody. The use of conditioned medium from cells previously exposed to PM(2.5) demonstrates that PM(2.5)-exposed cells release soluble EGFR ligands able to induce GM-CSF release by an autocrine manner. It was further demonstrated by inhibiting tumour-necrosis factor-alpha converting enzyme (TACE) that is involved in some EGFR ligand shedding. TAPI-2 and GM-6001, two TACE inhibitors, prevented the PM(2.5)-induced GM-CSF release as well as the silencing of TACE by siRNA. We provide evidence that the pro-inflammatory response induced by PM(2.5) exposure on HBE cells, results from an autocrine effect of EGFR ligands released by TACE activity. This autocrine loop by eliciting and sustaining inflammation could contribute to exacerbation of airway remodelling in respiratory-compromised individuals.

Physico-chemical characterization of African urban aerosols (Bamako in Mali and Dakar in Senegal) and their toxic effects in human bronchial epithelial cells: description of a worrying situation

“…This induction was previously associated with organic compounds of particles and their ability to induce reactive oxygen species (ROS) overproduction [36,37], an effect also evaluated in this study.…”

“…Previous studies at the laboratory demonstrated that PM 2.5 of different sites induced AREG mRNA expression in 16HBE cells and primary human bronchial epithelial cells NHBE [16,34] and was implicated in the persistence of GM-CSF pro-inflammatory response [35,36]. Consequently, its overexpression was suspected of participating in airway epithelium remodeling.…”

Insights in particulate matter‐induced allergic airway inflammation: Focus on the epithelium

“…However, there is still some controversy regarding the role of the NLPR3 inflammasome upon pollutant exposure . Alternatively, ambient PM can also enhance the expression and activation of different membrane‐associated receptors, such as the epidermal growth factor receptor (EGFR) . Dimerization of the EGFR will stimulate tyrosine kinase activity that can elicit PI3K/AKT signalling and mitogen‐activated protein kinases (MAPK) (ie ERK, JNK and p38), both involved in the activation of the transcription factor NF‐κB .…”

“…58,59 Alternatively, ambient PM can also enhance the expression and activation of different membrane-associated receptors, such as the epidermal growth factor receptor (EGFR). [60][61][62][63][64][65] Dimerization of the EGFR will stimulate tyrosine kinase activity that can elicit PI3K/AKT signalling and mitogenactivated protein kinases (MAPK) (ie ERK, JNK and p38), both involved in the activation of the transcription factor NF-jB. 30,63,[66][67][68][69] Importantly, after internalization or PRR activation, exposure to ambient PM/DEPs will activate oxidative stress responses in the airway epithelial cells.…”

The Secretome of Human Bronchial Epithelial Cells Exposed to Fine Atmospheric Particles Induces Fibroblast Proliferation

“…Moreover we demonstrated that EGFR ligands have an autocrine effect on the epithelium leading to a sustained pro-inflammatory response and mucus production [6,7]. The increased EGFR ligands expression induced by PM exposure could also act as a potent mitogenic factor for fibroblasts as some experimental studies have implicated EGFR signaling in pulmonary fibrosis [8].…”