Hyperactivation of sympathetic nerves fuels basophil infiltration in atopic dermatitis.

Abstract

Emotional stress exacerbates atopic dermatitis (AD) and contributes to overall disease burden. While sympathetic nervous system (SNS) activity broadly interacts with emotional states, its role in skin immunity remains underexplored. Using a murine model of AD-like disease, we demonstrated that skin inflammation triggered anxiety-like behaviors and hyperactivation of peripheral SNS innervating the affected skin. Disruption of peripheral SNS signaling, either by denervation or anxiety-relief interventions, markedly attenuated skin inflammation. Mechanistically, basophils were identified as key effector cells regulated by SNS activity. Norepinephrine activated β2-adrenergic receptors to enhance basophil motility and the chemokine C-C motif chemokine ligand (CCL)6-C-C motif chemokine receptor (CCR)1 axis, thereby promoting skin inflammation. In human AD, sympathetic nerve remodeling was observed in skin lesions, and basophil-associated CCL23 (the human ortholog of murine CCL6) and CCR1 correlated with disease severity. These findings define an SNS-basophil axis that links emotional states to skin inflammation, highlighting autonomic regulation as a therapeutic target for chronic skin diseases.