Investigating interferon lambda (IFN-γ) as a novel anti-inflammatory modulator of the skin barrier-immune-microbiome axis in atopic dermatitis 2309532

Abstract Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disease driven by type 2 (Th2)-mediated immune dysregulation, epidermal barrier dysfunction and microbial dysbiosis. While current therapies suppress acute inflammation, they often fail to restore the coordinated barrier—immune—microbiome homeostasis underlying chronic disease persistence. Interferon lambda (IFN-γ), a type III interferon with epithelial-restricted receptor expression, has emerged as a potential multi-axis immunomodulator capable of enhancing barrier function, limiting Th2-associated immune activation and restricting pathogenic microbial overgrowth. However, its integrated effects have not been evaluated in vivo in AD. We hypothesized that topical IFN-γ treatment would restore skin homeostasis by attenuating Th2-driven inflammation. Methods An MC903-induced AD model was established in C57BL/6 mice receiving topical IFN-γ or vehicle control during disease induction. Disease severity was assessed longitudinally by standardized clinical scoring. Barrier integrity was evaluated by histological analysis and expression of barrier-associated genes. Th2-associated immune responses were assessed in lesions and draining lymph nodes using multiplex cytokine assays and flow cytometry. Cutaneous microbial composition was analyzed through 16S rRNA sequencing. Results Topical IFN-γ treatment reduced clinical disease severity and epidermal hyperplasia compared with controls. IFN-γ—treated mice exhibited decreased Th2-associated cytokine expression and reduced inflammatory immune cell infiltration. Microbiome analysis revealed reduced S. aureus abundance and increased microbial diversity in IFN-γ—treated groups, indicating partial restoration of microbial homeostasis. Conclusion These findings demonstrate that IFN-γ functions as an epithelial-targeted immunomodulator capable of improving barrier integrity, suppressing Th2-immune signalling and restoring microbial balance in AD, supporting its potential as a multi-target therapeutic strategy. Funding Source Canadian Institutes of Health Research (CIHR) Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)