Xiao-Qing-Long-Tang alleviates allergic rhinitis by inhibiting M1 macrophage polarization and modulating the TRPV1 channel.

Abstract

BACKGROUND: Allergic rhinitis (AR) is a common IgE-mediated inflammatory disease of the nasal mucosa, involving immune-neural interactions such as mast cell activation, cytokine release, and transient receptor potential vanilloid 1 (TRPV1)-mediated neuronal sensitization. Xiao-Qing-Long-Tang (XQLT) is a classical traditional Chinese medicine used clinically for AR. However, its mechanisms, particularly in macrophage regulation and TRPV1 activity, remain not fully understood. OBJECTIVE: This study aimed to evaluate the therapeutic effects of XQLT in an ovalbumin (OVA)-induced AR mouse model and to investigate its molecular mechanisms focusing on immune regulation, macrophage-mediated inflammation, and TRPV1 channel activity. METHODS: The chemical composition of XQLT was analyzed by UPLC-Q Exactive Orbitrap-HRMS system. The therapeutic effectiveness of XQLT was assessed in an OVA-induced AR mouse model. Clinical symptoms, serum biomarkers (OVA-sIgE, interleukin-4 (IL-4), histamine), and histopathological changes were assessed. Transcriptomic analysis of nasal mucosa was performed to explore molecular pathways. The anti-inflammatory effects of XQLT were evaluated in LPS-stimulated RAW264.7 and bone marrow-derived macrophages by measuring NO, cytokine expression, and NF-κB activation. TRPV1 involvement was examined using immunohistochemistry in AR mice model, calcium imaging in HEK293 cells overexpressing TRPV1, as well as molecular docking. RESULTS: XQLT treatment significantly reduced nasal rubbing and sneezing frequencies in AR mice, decreased serum OVA-sIgE, IL-4, and histamine levels, and ameliorated nasal and lung histopathological remodeling without observable toxicity. Transcriptomic profiling revealed that XQLT modulated DEGs associated with immune response, inflammatory signaling, olfactory transduction, and sensory perception of pain. In macrophages, XQLT suppressed LPS-induced NO production, downregulated IL-6, IL-1β, CCL2, iNOS, and COX-2 expression, and inhibited NF-κB nuclear translocation. Importantly, XQLT reduced TRPV1 expression in AR nasal mucosa and inhibited TRPV1-mediated calcium influx in HEK293 TRPV1-overexpressing cells. Zingiberis Rhizoma (Ganjiang) was identified as a key herb contributing to TRPV1 inhibition in XQLT, supported by molecular docking analysis. CONCLUSION: XQLT alleviates AR symptoms and tissue remodeling through coordinated suppression of macrophage-mediated inflammation and TRPV1-dependent neurogenic pathways. These findings provide novel mechanistic insights into XQLT as a safe and promising multi-target therapy for AR.