Prolactin drives the pathogenic amplification of atopic dermatitis by promoting CCL17 secretion through activation of...

Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disorder driven by a combination of epidermal barrier dysfunction, immune dysregulation, and psychological stress. Although neuro-endocrine-immune interactions are known to contribute to the pathogenesis of AD, the key endocrine mediators and their molecular mechanisms require elucidation. Prolactin (PRL), a stress-associated hormone with cytokine-like immunomodulatory properties, has not been fully characterized in the context of AD.

This study integrated analyses of clinical samples, an MC903-induced AD-like mouse model, primary keratinocyte functional assays, and keratinocyte-specific Prlr conditional-knockout (CKO) mice. PRL/PRL receptor (PRLR) expression, inflammatory cytokine levels, and histopathological changes were assessed using RNA sequencing (RNA-seq) analysis, gene set enrichment analysis, and western blotting, immunofluorescence, and flow cytometry analyses to delineate the underlying mechanisms. In vivo interventions, including inhibition of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) pathway and CC chemokine ligand 17 (CCL17) neutralization, were employed to evaluate their roles in PRL-mediated inflammatory responses.

Patients with AD and AD-like mice exhibited markedly elevated PRL and PRLR levels, and PRL concentrations were positively correlated with disease severity and indicators of psychological stress. PRL activated the PI3K-AKT-nuclear factor kappa B (NF-κB) pathway and upregulated CCL17 expression in keratinocytes in vitro and exacerbated MC903-induced dermatitis in vivo by increasing interleukin (IL)-4, IL-13, and thymic stromal lymphopoietin (TSLP) levels. In contrast, Prlr-CKO mice showed attenuated skin inflammation and reduced Th2 cytokine expression upon MC903 stimulation. RNA-seq further revealed significant enrichment of the PI3K-AKT pathway in PRL-treated skin, with CCL17 being the most strongly upregulated chemokine. Neutralization of CCL17 markedly alleviated dermatitis and reduced Th2 cell infiltration, confirming the essential role of CCL17 in PRL-driven inflammation.

This study provides the first systematic evidence showing that the PRL/PRLR signaling axis amplifies AD-like skin inflammation by activating the PI3K-AKT-NF-κB pathway and inducing CCL17 expression, thereby promoting Th2-driven immune responses. Thus, keratinocyte-expressed PRLR is a central hub linking stress responses to cutaneous inflammation, and both PRLR and CCL17 represent promising therapeutic targets for AD, particularly in stress-associated disease phenotypes.