Dioscin alleviates allergic airway inflammation with IL-4R-associated modulation of epithelial-immune responses

Allergic asthma is characterized by airway inflammation, epithelial barrier dysfunction, and dysregulated immune responses. While Th2 cytokines and IL-4 receptor (IL-4R) signaling are central to its pathogenesis, accumulating evidence underscores the involvement of epithelial-immune interactions, metabolic disturbances, and gut-lung axis dysregulation. Dioscin, a natural steroidal saponin, has demonstrated anti-inflammatory properties, but its role in airway inflammation remains insufficiently explored.

We established an ovalbumin (OVA)-induced asthma model in BALB/c mice to assess the effects of dioscin on airway function, epithelial integrity, immune cell distribution, and mucosal inflammation. Lung metabolomics and 16S rRNA gene sequencing were conducted to evaluate metabolic and microbiota profiles. In vitro, two co-culture models were established: BMDCs-BEAS-2B to evaluate epithelial-immune crosstalk under IL-4R modulation, and BMDCs-RBL-2H3 to assess mast cell-associated immune responses under LPS/IL-4 stimulation with altered IL-4R expression.

Dioscin administration was associated with reduced airway hyperresponsiveness, inflammatory infiltration, oxidative stress, and Th2/Th17-related cytokine levels. Lung metabolomics revealed that dioscin partially restored OVA-induced metabolic imbalances, particularly in glutathione and purine metabolism pathways. 16S rRNA sequencing showed a partial recovery of microbial diversity and composition. Immune profiling indicated a shift in CD86⁺/CD206⁺ immune-cell phenotype ratio and reduced eosinophil and CD4⁺IL-4⁺ T cell infiltration. In BEAS-2B co-cultures, IL-4R expression modulated epithelial responsiveness to inflammatory cues and dioscin. In addition, the RBL-2H3 system allowed the evaluation of mast cell degranulation and FcεRI-related signaling, which were also influenced by IL-4R levels.

This study shows that dioscin alleviates allergic airway inflammation and is associated with improved epithelial integrity, reduced oxidative stress, and attenuated immune dysregulation. In vitro co-culture experiments suggest that IL-4R expression modulates the magnitude of epithelial-immune responses, but the current data do not establish a direct IL-4R-dependent mechanism in vivo; the metabolomic and microbiota findings should be interpreted as exploratory system-level associations rather than definitive mechanistic evidence. These findings provide insights into mucosal immunoregulation and natural compound-based interventions for allergic airway disease.