Background: Olfactory dysfunction (OD) is commonly associated with chronic rhinosinusitis (CRS), with T-helper 2 (Th2) cell polarization implicated in its pathogenesis. This study aimed to elucidate the role and underlying mechanism of the Th2-derived cytokine interleukin (IL)-4, acting via the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, in mediating olfactory epithelial injury during CRS-related OD.

Methods: The mechanism of Th2 cell dominance in CRS-associated OD through the IL-4/PI3K signaling pathway was investigated. A CRS model was established in age-matched senescence accelerated mouse resistant 1 (SAMR1) mice, with sneezing and scratching frequencies recorded. Flow cytometry quantified Th cell proportions and apoptosis, while quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blotting (WB) assessed IL-4/interleukin-4 receptor (IL-4R), IL-4/PI3K pathway components, inflammatory/apoptotic markers, and olfactory-associated proteins. Following transfection of IL-4R short hairpin RNA (shRNA) into olfactory epithelial cells (efficiency confirmed by RT-qPCR and WB), a Th2 cell-olfactory epithelial cell co-culture system was established.

Results: CRS mice exhibited decreased olfactory marker protein (OMP) expression, upregulated phosphorylated- nuclearfactor-kappaB p65 (p-p65), enhanced IL-4/PI3K pathway activity, and elevated inflammatory/apoptotic markers. Th2 co-culture reduced olfactory epithelial cell viability, increased apoptosis, activated IL-4/PI3K signaling and inflammatory/apoptotic responses, and suppressed OMP expression. Notably, IL-4R knockdown reversed these alterations.

Conclusions: CRS modeling and Th2 co-culture reduces OMP expression, activates the p-p65/IL-4/PI3K pathway, and exacerbates inflammation and apoptosis, whereas IL-4R knockdown effectively counteracts these alterations.