TET2 deletion in the olfactory bulb aggravates olfactory impairment in mice with cigarette smoke-induced nasal polyps.

BACKGROUND: Cigarette smoke (CS) is a key environmental risk factor for olfactory impairment, yet its underlying mechanisms in chronic rhinosinusitis with nasal polyps (CRSwNP) remain incompletely understood. OBJECTIVE: To elucidate the pathogenesis involving TET2 in CS-induced olfactory impairment. METHODS: A mouse model for nasal polyps (NPs) was established in wild-type (WT) and Tet2 knockout (Tet2-/-) mice followed by CS exposure. Olfactory function was assessed behaviorally, and the expression of olfactory marker protein (OMP) in the olfactory epithelium was examined. The activation of microglia, neuroinflammation, and neuronal damage in the olfactory bulb were evaluated using immunofluorescence, TUNEL staining, ELISA, and Western blot. DNA hydroxymethylation levels were analyzed by Dot blot and hydroxymethylated DNA immunoprecipitation-quantitative PCR (hMeDIP-qPCR). The effects of nicotine on TET2, GPX4, and SLC7A11 expression and the underlying mechanisms were also explored. RESULTS: Tet2 knockout significantly exacerbated CS-induced olfactory impairment, as evidenced by a more pronounced reduction in olfactory ability and increased incidence of polypoid changes and goblet cell hyperplasia. However, the expression of OMP in the olfactory epithelium remained unaffected. Compared with WT mice stimulated by CS, Tet2 knockout mice exhibited more increased microglial activation and neuroinflammation in the olfactory bulb, characterized by elevated levels of IL-1β, IL-6, and TNF-α. Moreover, TET2 deletion aggravated neuronal damage in the olfactory bulb, as evidenced by increased neuronal apoptosis and nicotine accumulation. Mechanistically, TET2 deletion potentiated ferroptosis in the olfactory bulb by downregulating GPX4 expression, while SLC7A11 expression was not affected. Nicotine was found to downregulate GPX4 expression in microglia and olfactory bulb neurons via TET2-mediated DNA demethylation, thereby inducing ferroptosis. CONCLUSION: Depletion of TET2 in the olfactory bulb aggravates CS-induced downregulation of GPX4, and the subsequent induction of ferroptosis may represent a critical mechanism underlying the exacerbation of olfactory impairment in CRSwNP.