Fine PM induce airway MUC5AC expression through the autocrine effect of amphiregulin
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Particulate pollution is suspected to contribute to obstructive lung diseases characterized by chronic inflammation, mucus hypersecretion and bronchial remodeling. Our aim was to study the effect of real-world particulate matter (PM) on the expression of a mucin, MUC5AC, focusing on the role of the epidermal growth factor receptor (EGFR) pathway. MUC5AC induction was studied in vivo in mice trachea and in vitro in human bronchial epithelial cells (HBEC) exposed to urban fine PM. Fine PM were able to induce MUC5AC mRNA in mice trachea after 48 h of exposure (50 μg PM/mouse), and MUC5AC mRNA and protein in HBEC after 24 h of exposure (from 5 μg PM/cm2). It was associated with the increased expression of amphiregulin (AREG), an EGFR ligand. Experiments with conditioned media (media from PM-treated cells) demonstrated the involvement of AREG on MUC5AC induction as MUC5AC induction by media from PM-treated cells was prevented in the presence of either EGFR- or AREG-neutralizing antibodies. The effect of an inhibitor of a metalloprotease involved in the AREG shedding confirmed the autocrine loop made by AREG leading to MUC5AC induction by fine PM. We also demonstrated that IL-8 pro-inflammatory cytokine induction was dependent on the same autocrine mechanisms. We demonstrate for the first time that MUC5AC expression and production is increased by short-term exposure to fine PM through an autocrine effect of AREG. Our study provides mechanistic explanations to the exacerbation of obstructive lung diseases induced by particulate pollution characterized by mucus hypersecretion and chronic inflammation.
KeywordsAtmospheric particle EGFR pathway Lung Mucin Pro-inflammatory cytokine
This work was supported by Agence Nationale pour la Recherche (ANR) Megatox (ANR CESA 2008-009-02), ADEME and ANSES French environmental agencies for Val S. PhD funding. ANSES also supported Belade E. PhD funding. Jorge Boczkowski was supported by a “Contrat Hospitalier de Recherche Translationnelle” (Inserm—APHP). The authors want to thank the Jacques Monod Institute (IJM, Paris, France) for the use of Genomic facility and Flow Cytometry facility with the help of Nicole Boggetto.
Conflict of interest
The authors declare no conflicts of interest.
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