Abstract Title: Vagus Nerve Stimulation Ameliorates Inflammatory Skin Diseases through Systemic Anti-Inflammatory Pathways: Evidence from Murine Models of Psoriasis and Atopic Dermatitis William J. Nahm,1 Ki Joong Kim,2 Eui Namgung,3 Vincent Falanga,4

1) New York University Grossman School of Medicine, New York, NY, USA 2) Department of Oriental Medicine, Daejeon University, Daejeon, ROK 3) Department of Physics, University of California, San Diego, La Jolla, CA, USA 4) Department of Dermatology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA

Background: The cholinergic anti-inflammatory pathway, activated through vagus nerve stimulation (VNS), plays a crucial role in immune response regulation. Although the skin lacks direct vagal nerve (VN) innervation, VNS may influence cutaneous inflammatory disorders through indirect mechanisms. In recent years, VNS has shown promise in modulating rheumatoid arthritis, inflammatory bowel disease, and other conditions, such as cardiovascular disease. This study investigated whether VNS could improve inflammatory skin diseases by modulating systemic inflammatory responses and local inflammatory cytokines.

Methods: Two distinct murine models were employed: C57/BL6 mice with imiquimod-induced psoriasis lesions and NC/Nga mice with dinitrochlorobenzene (DNCB)-induced atopic dermatitis. In the imiquimod model, psoriasis-like lesions were induced by applying imiquimod 5% cream to shaved dorsal skin for seven consecutive days, followed by every other day for six days. The DNCB model involved sensitization with 1% DNCB for seven days, followed by 0.3% DNCB for three days, resulting in marked scaling, crusting, and exudate formation. Cervical VNS (5V/5mA/5Hz/5ms/5min) was administered at 6- and 24-hour pre-sacrifice in the imiquimod model, and 24 hours pre-sacrifice in the DNCB model. Outcomes were assessed through clinical evaluation, histological analysis, immunofluorescence staining, western blotting, and cytokine measurement in plasma and splenic tissue.

Results: The application of imiquimod and DNCB produced psoriatic and eczematous-type clinical inflammation, accompanied by markedly increased epidermal thickening. VNS significantly reduced epidermal thickening and attenuated clinical manifestations in both models. In the imiquimod model, VNS produced a moderate reduction of erythema, scaling, and crusting. The DNCB-induced dermatitis was dramatically ameliorated following VNS treatment. Both models demonstrated significant reduction in pro-inflammatory cytokine expression (TNF-α, IL-6, IL-1β) and decreased CD11b-positive cutaneous macrophage infiltration. Immunofluorescence confirmed decreased epidermal TNF-α expression post-VNS. A single VNS application in DNCB-treated mice resulted in a 32% reduction in plasma TNF-α concentrations (p < 0.01). Notably, the protein levels of TNF-α and IL-1β, which were elevated in splenic tissue in both inflammatory models, were subsequently downregulated by VNS treatment.

Conclusion: These findings establish VNS as a promising therapeutic approach for inflammatory skin diseases. The therapeutic effects appear to be mediated through the modulation of systemic and subsequently local inflammation. These findings suggest that cutaneous inflammatory disorders may be linked to systemic inflammatory processes, providing mechanistic insights into the anti-inflammatory effects of VNS in dermatological conditions. Additionally, VN dysregulation emerges as a potential unifying mechanism underlying the well-established association between inflammatory skin diseases and their systemic comorbidities.