Targeting IL-33/ST2/NF-κB Axis and Mast Cell Activation: Quercetin's Therapeutic Mechanism in Allergic Rhinitis(PONE-D-25-35392)

AbstractBackground: Allergic rhinitis (AR) is driven by immunoglobulin E (IgE)-mediated mast cell (MC) activation, leading to degranulation and type 2 cytokine release. Quercetin has shown anti-allergic effects, but its precise mechanism in AR remains incompletely understood.Methods: Quercetin's impact on interleukin-33 (IL-33)-stimulated rat basophilic leukemia-2H3 (RBL-2H3) cells was assessed using both direct IL-33 exposure and IgE-mediated activation via anti-dinitrophenyl (DNP)-IgE sensitization and DNP- conjugated human serum albumin (HSA) challenge. Cytokine secretion, degranulation, apoptosis, and expression of IL-33 /suppression of tumorigenicity 2 (ST2)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway components were assessed using enzyme-linked immunosorbent assay (ELISA), Western blotting, and reverse transcription quantitative polymerase chain reaction (RT-qPCR). A mouse model of AR induced by ovalbumin (OVA) was employed to assess in vivo efficacy. Symptom scores, inflammatory cytokine levels, nasal mucosal histology, and key signaling molecule expression were analyzed to confirm quercetin's protection.Results: Quercetin significantly suppressed IL-33-induced cytokine production, degranulation, and apoptosis in vitro; these effects were partially reversed by ST2 overexpression. In vivo, quercetin alleviated AR symptoms, reduced serum T helper 2 (Th2) cytokines, OVA-specific IgE (OVA-sIgE), and IL-33 levels, improved histopathology, and downregulated IL-33/ST2/NF-κB pathway proteins in nasal tissues.Conclusion: Our findings demonstrate quercetin's anti-allergic effects against AR, which are likely mediated through suppression of mast cell activation and inhibition of the IL-33/ST2/NF-κB signaling cascade.