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

Area of Science:

• Immunodermatology
• Neuroendocrinology
• Molecular Biology

Background:

• Stress is a known trigger for skin inflammation and disease flares, but the underlying mechanisms are not fully understood.
• Identifying the molecular links between stress and skin inflammatory responses is crucial for developing effective treatments.

Purpose of the Study:

• To elucidate the mechanistic pathway linking stress to skin inflammation.
• To identify key molecular mediators and cellular players involved in stress-induced skin inflammation.
• To explore potential therapeutic targets for mitigating stress-exacerbated skin inflammation.

Main Methods:

• Utilized human data and mechanistic exploration in mouse models of skin inflammation.
• Employed single-cell RNA sequencing to analyze cellular responses under stress.
• Investigated the role of prolactin, NR4A1, and midkine in stress-induced skin inflammation.

Main Results:

• Prolactin, elevated in stressed individuals and mice, acts as a key mediator linking stress to skin inflammation.
• Prolactin activates the NR4A1 transcription factor in APCDD1+ fibroblasts, leading to midkine secretion.
• This NR4A1-midkine axis amplifies immune cell infiltration and inflammatory responses in the skin.
• Targeting NR4A1 or midkine effectively reversed inflammatory effects in vivo.

Conclusions:

• A novel mechanism reveals prolactin as a key mediator of stress-induced skin inflammation via the NR4A1-midkine axis in dermal fibroblasts.
• NR4A1 and midkine are identified as crucial components in the amplification of skin inflammation under stress.
• NR4A1 and midkine represent promising therapeutic targets for managing stress-related skin inflammation and disease flares.