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

TL;DR

Stress worsens skin inflammation by activating a prolactin-NR4A1-midkine pathway in fibroblasts, offering new targets for treatment.

Contribution

Identifies a novel stress-induced prolactin-NR4A1-midkine axis in fibroblasts that exacerbates skin inflammation.

Findings

Prolactin levels increase in stressed psoriasis patients and mice, activating NR4A1 in APCDD1+ fibroblasts.

NR4A1 activation promotes midkine secretion, which amplifies immune responses and inflammation.

Blocking NR4A1 or midkine reverses stress-induced inflammation in mouse models.

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.

Chronic psychological stress activates prolactin signaling to reprogram dermal fibroblasts into APCDD1
+ inflammatory effectors via NR4A1, driving midkine secretion. This paracrine hub amplifies keratinocyte proliferation and immune recruitment, thus exacerbating skin inflammation. Therapeutic inhibition of the NR4A1‐midkine axis not only neutralizes stress‐induced inflammation but nominates APCDD1
+ fibroblasts as the previously unrecognized targets for intercepting neuroendocrine‐immune circuit.

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