Sympathetic nerve dysfunction exacerbates skin inflammation in atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disorder with severe itching, posing a great burden on both the physical and mental health of patients. AD is frequently complicated by sympathetic nervous system (SNS) dysfunction.

We sought to explore the interplay between skin inflammation and SNS activity during AD development.

Using clinical cohort data and murine models, we used impression mold technique, simultaneous noninvasive recording of electrocardiogram and skin sympathetic nerve activity, ultrasound, immunohistochemistry, and RNA sequencing to investigate the impact of AD inflammation on sympathetic function and structure. Conversely, chemogenetic manipulations were used to assess the effects of the SNS on AD-related inflammation and itch.

We revealed significant SNS dysfunction in patients with AD, which was manifested by diminished perspiration and attenuated electrical responses, and ultrasound data showed compensatory hypertrophy in the sympathetic ganglia. These impairments were partially reversed in patients with AD treated with dupilumab. Moreover, MC903-induced AD-like dermatitis exhibited histologic and molecular indications of inflammatory stress and injury in the sympathetic ganglia. Chemogenetic inhibition of Phox2b⁺ sympathetic neurons exacerbated MC903-induced cutaneous inflammation and itch sensation in mice, whereas targeted activation of sympathetic neurons attenuated both clinical and histologic manifestations of AD-like dermatitis.

Our data revealed a detrimental cycle between AD skin inflammation and sympathetic nerve dysfunction.