Stress‐Induced Activation of Prolactin‐NR4A1‐Midkine Axis Exacerbates Skin Inflammation

Abstract Stress is an established trigger of skin inflammation and disease flares; however, the mechanisms have remained unclear. Here, using human data, mechanistic exploration, and single‐cell RNA sequencing in mouse models of skin inflammation under stress challenge, prolactin is identified as a key mediator linking stress to inflammatory responses in the skin through an NR4A1‐midkine axis in APCDD1 ⁺ fibroblasts in the upper dermis. The data shows that prolactin is increased in the plasma of psoriasis patients with high levels of stress and in stressed mice, which activates transcription factor NR4A1 in APCDD1 ⁺ fibroblasts, promoting secretion of midkine, and amplification of immune infiltration and responses in neighboring cells. Targeting NR4A1 or midkine effectively reverses these inflammatory effects in vivo. These data provide a novel mechanism for stress‐related amplification of skin inflammation and identify NR4A1 and midkine as potential therapeutic targets to mitigate stress‐exacerbated inflammation.