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

Abstract

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.