DEP-induced ZEB2 promotes nasal polyp formation via epithelial-to-mesenchymal transition

Mingyu Lee, Suha Lim, Yi Sook Kim, Roza Khalmuratova, Seung-Hyun Shin, Iljin Kim, Hyun-Jik Kim, Dong-Young Kim, Chae-Seo Rhee, Jong-Wan Park, Hyun-Woo Shin
Journal of Allergy and Clinical Immunology 2021 May 3

BACKGROUND: Diesel exhaust particles (DEP) are associated with the prevalence and exacerbation of allergic respiratory diseases, including allergic rhinitis and allergic asthma. However, DEP-induced mechanistic pathways promoting upper airway disease and their clinical implications remain unclear OBJECTIVE: We sought to investigate the mechanisms by which DEP exposure contributes to nasal polyposis using human-derived epithelial cells and a murine nasal polyp (NP) model.

METHODS: Gene set enrichment and weighted gene co-expression network analyses were performed. Cytotoxicity, epithelial-to-mesenchymal transition (EMT) markers, and nasal polyposis were assessed. Effects of DEP exposure on EMT were determined using epithelial cells from normal or CRS patients with or without NPs. BALB/c mice were exposed to DEP through either a nose-only exposure system or nasal instillation, with or without house dust mite (HDM), followed by ZEB2 shRNA delivery.

RESULTS: Bioinformatics analyses revealed that DEP exposure triggered EMT features in airway epithelial cells (AECs). Similarly, DEP-exposed human nasal epithelial cells (hNECs) exhibited EMT characteristics, which were dependent on ZEB2 expression. hNEC-derived from chronic rhinosinusitis (CRS) patients presented more prominent EMT features after DEP treatment, when compared to those from control subjects and NP patients. Co-exposure to DEP and HDM synergistically increased the number of NPs, epithelial disruptions, and ZEB2 expression. Most importantly, ZEB2 inhibition prevented DEP-induced EMT, thereby alleviating NP formation in mice.

CONCLUSIONS: Our data show that DEP facilitated NP formation, possibly via the promotion of ZEB2-induced EMT. ZEB2 may be a therapeutic target for DEP-induced epithelial damage and related airway diseases, including NPs.

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