A Neuroimmune Link Explains How Stress Gets Under the Skin in Eczema

Many people are familiar with this prickly pattern: A deadline creeping closer, a sleepless night, or some other stressful situation causes skin to act up. What often starts as itchiness gives way to an eczema flare-up, complete with an angry, red, dry rash.

But what is the biology behind psychological stress aggravating skin inflammation? Shenbin Liu, a neuroimmunologist at Fudan University, set out to find the answer.

Now, by analyzing patient data and modeling this condition in animals, Liu and his team found that mental strain activates a subset of neurons in the skin, which recruit immune cells called eosinophils that exacerbate inflammation.¹ Their findings, published in Science, highlight a link between psychological stress and skin inflammation and offer potential targets to treat stress-induced worsening of skin diseases.

“Integrating mental health evaluations with strategies aimed at reducing stress, anxiety, and depression could represent an effective, though underutilized, approach to improving outcomes after dermatitis treatment,” noted the authors in the paper.

Using an established scale, Liu and his team first assessed the stress levels in 51 patients with atopic dermatitis (AD), the most common type of eczema. Those with higher stress levels had more severe skin inflammation, determined by greater water loss, scratching, and presence of activated immune cells, as well as heightened eosinophil counts in their skin tissue and blood.

The researchers turned to mice models of AD to investigate the mechanisms underlying these observations. They exerted psychological stress on mice by repeatedly placing the animals on an elevated, unstable platform and found that this heightened inflammation and eosinophil counts in the skin. Genetically depleting eosinophils calmed inflammation even in stressed mice.

Next, Liu and his team investigated how the brain transmits stress signals to the skin to attract eosinophils. The researchers hypothesized a role for skin-innervating sympathetic neurons, which respond to brain stimuli and cause goosebumps or sweating. Treating mice with chemicals to deplete sympathetic neurons rendered them resistant to stress-induced inflammation and eosinophil accumulation.

Single-nucleus RNA sequencing indicated that stress activated a subpopulation of neurons expressing the hormone prodynorphin (Pdyn⁺ neurons), which regulate key processes like reward, pain, emotion, and stress. Using a toxin to deplete this neuronal subpopulation in mice did not increase skin inflammation upon exposing the animals to psychological stress.

Finally, optogenetic activation of Pdyn⁺ neurons enhanced eosinophil recruitment to the skin and worsened inflammation, indicating that stress-induced Pdyn⁺ neuron activation exacerbates skin inflammation through eosinophils.

In a related Perspective article, University of Toulouse neuroimmunologists Nicolas Gaudenzio and Lillan Basso, who were not associated with the study, wrote, “[The authors] offer a mechanistic explanation for the well-documented but poorly understood link between stress and atopic dermatitis flare-ups.”²