Dexamethasone modulates chemokine networks in murine type 2 inflammation model: Integration of network pharmacology and in vivo validation

Background: Type 2 nasal inflammatory diseases, including allergic rhinitis and chronic rhinosinusitis, are driven by cytokine and chemokine networks that sustain mucosal inflammation. Glucocorticoids serve as anti-inflammatory therapies, yet how they modulate chemokine networks has not been systematically evaluated using integrative approaches. Objective: This study aimed to elucidate the dose-dependent modulation of type 2 inflammation and specific chemokine pathways by dexamethasone in nasal inflammatory diseases, integrating network pharmacology with in vivo validation. Methods: Network pharmacology was used to predict core targets and pathways of dexamethasone related to type 2 nasal inflammation. Subsequently, in a papain-induced mouse model of type 2 inflammation, dexamethasone was administered intraperitoneally at 1, 5, or 10 mg/kg. Pharmacodynamic effects were assessed via evaluation of eosinophil and goblet cell infiltration, and the expression of inflammatory cytokines and chemokines. Results: Network pharmacology identified a chemokine-centered mechanism of glucocorticoids in allergic rhinitis/chronic rhinosinusitis, with CCL11 and the CCL2/CCR2 axis among hub nodes. In animal model, dexamethasone produced a clear dose–response hierarchy. Transcriptionally, 10 mg/kg dexamethasone significantly reduced Ccl2 and Ccr2 mRNA and downregulated Ccl11 and key type 2 cytokine/alarmin transcripts. At the protein level, CCL11 was significantly decreased at 5 mg/kg, whereas CCR2 was suppressed only at 10 mg/kg; CCL2 protein remained unchanged across groups. Systemically, leukocyte redistribution was evident from 5 mg/kg upward. Histologically, marked attenuation of nasal eosinophil infiltration and goblet cell hyperplasia was observed mainly at 10 mg/kg within the 4-day intervention window. Conclusion: Integrating network pharmacology with in vivo validation supports a chemokine-centered regulatory network engaged by dexamethasone in type 2 nasal inflammation. The suppression of CCL11 at intermediate doses identifies it as a sensitive pharmacodynamic indicator, whereas rapid histologic resolution in this acute model requires higher dosages within a short therapeutic window.