A sympathetic-eosinophil neuroimmune axis orchestrates psychological stress to exacerbate skin inflammation

Psychological stress is hypothesized to trigger exacerbations of atopic dermatitis (AD). However, the neurobiological mechanisms linking stress to immune processes involved in atopy remain poorly understood. Here, we identified a subtype of skin-specific Prodynorphin (Pdyn)+ noradrenergic sympathetic neurons that closely interact with eosinophils, mediating the stress-induced aggravation of AD. Among AD patients, psychological stress was positively correlated with eosinophilic infiltration and the severity of inflammation. In AD-like murine models, genetic ablation of eosinophils or Pdyn+ sympathetic neurons mitigated stress-induced exacerbation of skin inflammation. Furthermore, optogenetic or chemogenetic activation of Pdyn+ sympathetic neurons precipitated AD inflammation through eosinophils. These neurons promote eosinophil recruitment via the CCL11-CCR3 axis and activate them through the noradrenaline-Adr2 pathway within the inflamed skin. Our findings uncover a neuroimmunological mechanism underlying psychological stress-induced exacerbation of AD, highlighting the Pdyn+ sympathetic-eosinophil axis as a crucial interface between the brain and skin inflammation, with potential therapeutic implications.