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

Cigarette smoke (CS) exposure is an important risk factor for the development of chronic rhinosinusitis with nasal polyp (CRSwNP). Previously, we found ten-eleven translocation 2 (TET2) deficiency exacerbates nasal polypogenesis by inducing epithelial-to-mesenchymal transition (EMT). However, whether smoking regulates nasal polyp (NP) formation through TET2 remains unknown. Here, we found that TET2 was more significantly down-regulated in human nasal epithelial cells (hNECs) and macrophages in smoking NP (S-NP) patients, compared with levels seen in normal volunteers or non-smoking NP (NS-NP) patients. Cigarette smoke extract (CSE) induced EMT in hNECs and the release of tissue remodeling related factors (MMP-2, MMP-7, MMP-9 and TGF-β1) by THP-1 cells, which were reversed by TET2 overexpression. Furthermore, CSE promoted tissue remodeling or ERK/P38 MAPK pathway rather than the JNK pathway, through inhibiting TET2 in hNECs and THP-1 cells. In a co-culture system of hNECs and THP-1 cells, THP-1 cells stimulated by CSE promoted EMT in hNECs, and these effects were reversed by ERK/P38 MAPK pathway inhibitors. In NP mice model, CS promoted NP formation by down-regulating TET2 and activating ERK/P38 MAPK pathway. Taken together, our study revealed that CS facilitated NP formation, possibly via down-regulating TET2 and activating ERK/P38 MAPK pathway. Thus, nasal epithelium TET2 loss might be a underlying mechanisms for CS-induced NPs.