Cigarette smoke exposure promotes nasal polyp formation through down-regulating TET2

Area of Science:

• Otorhinolaryngology
• Molecular Biology
• Toxicology

Background:

• Cigarette smoke (CS) is a risk factor for chronic rhinosinusitis with nasal polyps (CRSwNP).
• Ten-eleven translocation 2 (TET2) deficiency exacerbates nasal polyp formation by inducing epithelial-to-mesenchymal transition (EMT).
• The role of TET2 in CS-induced nasal polyp (NP) formation is currently unknown.

Purpose of the Study:

• To investigate the role of TET2 in CS-induced NP formation.
• To elucidate the molecular mechanisms underlying CS-induced NP development, focusing on the TET2 and ERK/P38 MAPK pathways.

Main Methods:

• Analysis of TET2 expression in human nasal epithelial cells (hNECs) and macrophages from NP patients with and without smoking history.
• In vitro studies using cigarette smoke extract (CSE) on hNECs and THP-1 cells to assess EMT and tissue remodeling factors.
• Overexpression of TET2 and inhibition of ERK/P38 MAPK pathway to evaluate their effects.
• Co-culture systems of hNECs and THP-1 cells.
• In vivo studies using a mouse model of NP exposed to CS.

Main Results:

• TET2 was significantly downregulated in hNECs and macrophages of smoking NP patients.
• CSE induced EMT in hNECs and release of tissue remodeling factors (MMP-2, MMP-7, MMP-9, TGF-β1) from THP-1 cells, effects reversed by TET2 overexpression.
• CSE inhibited TET2 and activated the ERK/P38 MAPK pathway in hNECs and THP-1 cells, promoting tissue remodeling.
• Inhibition of the ERK/P38 MAPK pathway reversed CSE-induced EMT in hNECs.
• CS promoted NP formation in mice by downregulating TET2 and activating the ERK/P38 MAPK pathway.

Conclusions:

• CS exposure downregulates TET2 in nasal tissues, contributing to NP formation.
• The ERK/P38 MAPK pathway is activated by CS, potentially mediating TET2 inhibition and promoting tissue remodeling in NPs.
• Loss of nasal epithelium TET2 may be a key mechanism in CS-induced NP development.