Quercetin improves macrophage immune regulatory functions to alleviate airway Th2 polarization

Th2 polarization is a central driver of allergic airway inflammation, yet the epigenetic mechanisms underlying its dysregulation remain poorly defined. Quercetin is a bioactive flavonoid with immunomodulatory properties. This study investigates whether quercetin alleviates Th2-driven pathology in allergic airway inflammation by targeting IL-10 promoter hypermethylation in airway M2 macrophages.

Using a murine model of house dust mite (Derf2)-induced allergic airway inflammation, we isolated airway M2 macrophages via flow cytometry and assessed their immunosuppressive capacity using CFSE-based T cell proliferation assays. Epigenetic regulation of Il10 was analyzed by bisulfite sequencing and chromatin immunoprecipitation. Quercetin (intranasal) was administered daily for 7 days.

Allergic mice exhibited impaired M2 cell-mediated T cell suppression (proliferation index: 85% vs. 34% in controls, P < 0.01) and IL-10 deficiency in bronchoalveolar lavage fluid (8.5 pg/ml vs. 28.2 pg/ml, P <0.001). Il10 promoter hypermethylation (72% vs. 35% methylation at CpG sites -200 to +100) and reduced KDM5A recruitment were observed in M2 cells from allergic mice. Quercetin treatment reversed these epigenetic defects, restoring KDM5A binding (P < 0.05) and Il10 transcription (2.1-fold increase, P < 0.01), thereby reducing Th2 cytokines and airway hyperresponsiveness.

Our findings identify KDM5A-mediated Il10 promoter demethylation as a critical mechanism for M2 cell immunoregulation in allergic airway inflammation. Quercetin alleviates Th2-driven pathology by restoring Il10 expression via epigenetic reprogramming of M2 macrophages. This study advances the understanding of natural compounds in targeting epigenetic checkpoints and provides a rationale for quercetin-based therapies in allergic diseases.