The mechanism of SMAD4/ERK pathway in regulating Th17/Treg cell differentiation leading to olfactory dysfunction in chronic rhinosinusitis

BACKGROUND: Chronic rhinosinusitis (CRS) is characterized by a high recurrence rate within five years post-surgery, posing a persistent challenge for otolaryngologists globally. Recent research has underscored the pivotal role of the Th17/Treg cell balance in the pathogenesis of CRS. This study aims to investigate the alterations in the Th17/Treg cell balance in CRS and elucidate the underlying molecular mechanisms. METHODS: CRS model was established to assess the levels of inflammatory cytokines, olfactory marker protein expression, SMAD4 expression, and ERK1/2 phosphorylation. We then overexpressed SMAD4 or treated CRS mice with ERK1/2 inhibitors, measuring the impact on Th17/Treg marker expression. Moreover, the influence of the SMAD4/ERK signaling axis on the Th17/Treg balance within the CD4 + T cell population was investigated. RESULTS: CRS mice exhibited significantly reduced olfactory marker protein and SMAD4 expression, alongside increased ERK1/2 phosphorylation. Histological analysis revealed an increased infiltration of eosinophils. Of particular note, the expression of Treg markers was markedly decreased, while Th17 marker expression exhibited a corresponding increase, suggesting a potential shift in the Th17/Treg balance. Interventions involving SMAD4 overexpression or ERK1/2 inhibition led to a reduction in eosinophil infiltration and successfully reversed the aberrant expression patterns of the aforementioned markers. Furthermore, SMAD4 knockdown resulted in a decreased proportion of Treg cells and an increased proportion of Th17 cells. This alteration in the Th17/Treg balance was effectively counteracted by ERK inhibitor. CONCLUSIONS: The deletion of SMAD4 regulates the differentiation of Th17/Treg cells via ERK1/2 phosphorylation, thereby exacerbating the olfactory dysfunction of CRS.