Patients and physicians have long known that psychological stress can exacerbate symptoms of atopic dermatitis (AD), but the exact mechanism has been unclear. New research utilizing mouse models and patient data sheds light on specific neural pathways that might be implicated in this process.

“Our study shows that psychological stress does not worsen skin inflammation through a vague, generalized stress response” but rather through a “biologically translated” mechanism, lead author Jiahe Tian, PhD, of the Institute of Brain Science, Fudan University, Shanghai, China, told Medscape Medical News.

The study was recently published online in Science.

Eosinophils Implicated

The skin has “dense neural and immune networks” and, as such, is “particularly susceptible to stress-induced dysregulation, as exemplified by AD,” the authors wrote.

Traditional models “attribute this interplay to generalized stress responses through the hypothalamus-pituitary-adrenal (HPA) axis or systemic immune dysfunction,” they noted. But these explanations, they added, “remain inadequate in explaining the specificity and severity of skin-targeted inflammation exacerbated by psychological stress.”

Tian said that she and her colleagues “wanted to understand not only whether psychological stress affects skin inflammation but also how it does so mechanistically.”

To investigate this question, they retrospectively studied 51 patients with AD, using the Perceived Stress Scale to measure stress levels and assessed the severity and extent of skin inflammation using the SCORing Atopic Dermatitis (SCORAD) calculator and the Numeric Rating Scale. Eosinophil levels were determined through blood and skin biopsies.

“In patients with inflammatory skin disease, higher stress levels were associated with more severe skin lesions,” Tian told Medscape Medical News. “This relationship was also strongly linked to increased eosinophils in both the blood and the skin, while other immune cells did not show the same pattern.”

This, she said, led the researchers “to ask a key question: how do stress signals in the brain reach the skin and shape local inflammation?”

Take Stress Seriously

They then subjected mice with an AD-like phenotype to three types of stressors during the inflammatory phase. All the stressors triggered the release of stress hormones, including corticosterone through the HPA axis and noradrenaline from the peripheral nervous system. But one particular stress condition, repeated high-platform stress (RHS), “elicited the most pronounced noradrenaline elevation, suggesting heightened sympathetic activation under this condition,” and was found to “markedly” exacerbate skin inflammation, they reported. 

Single-cell RNA sequencing of CD45-positive leukocytes taken from inflammatory skin lesions in RHS-exposed AD-like mice, as well as untreated controls, revealed that 20 different immune cell populations — including T and B cells, mast cells, and eosinophils — showed stress-related changes in gene expression patterns and cell numbers.

The researchers used independent flow cytometric analysis to evaluate mice that lacked T and B cells, as well as mice that were mast cell-deficient. They found that stress-induced changes continued to take place in these mice, pointing to the role of eosinophils in mediating the reaction.

This finding led them to focus on eosinophilia, and when they did, they discovered that stressed mice exhibited a twofold increase in eosinophil percentage and a fourfold risk in absolute eosinophil counts in inflamed skin. Moreover, directly stimulating eosinophils “was sufficient to trigger acute itch flare-ups in AD-like mice,” they wrote.

On the other hand, mice that had undergone genetic ablation of their eosinophils were protected against stress-exacerbated dermatitis, although baseline inflammation was unaffected. “These results suggested that psychological stress promotes eosinophil accumulation, exacerbating preestablished skin inflammation,” the authors commented.

Peripheral sympathetic nerves, rather than the HPA axis, were found to mediate the stress-induced worsening of skin inflammation.

The researchers further identified two major populations of noradrenergic sympathetic neurons. These were defined by prodynorphin (Pdyn) and neuropeptide Y (Npy) expression, which preferentially innervate hairy skin and were activated by psychological stress.

Optogenetic activation of Pdyn-positive neurons promoted the recruitment of eosinophils and exacerbated inflammation — effects that were eliminated “upon eosinophil depletion,” they wrote.

“We found that stress signals from the brain are transmitted to the skin by a specific neuron subset — the Pdyn-positive sympathetic neurons, which directly relay stress signals to the skin and promote the recruitment and activation of eosinophils by releasing neurotransmitters and chemotactic factors,” Tian said. “In turn, this process amplifies inflammation and worsens itch.” By contrast, the Npy-positive counterparts weren’t involved.

Focusing on specific chemokines released by Pdyn-positive neurons, the researchers identified the CCL11-CDR3 signaling pathway, which mediates eosinophil chemotaxis through the beta-2 adrenergic receptor. Removing these neurons, the beta-2 adrenergic receptor, or the eosinophils themselves, reduced stress-induced inflammation in the mice. “This study is still at the basic research stage,” Tian commented. “So its message is not simply telling patients that to ‘stress less’ will solve the problem. Skin inflammation is more complex than that.”

Instead, “what our findings do suggest is that psychological stress should be taken seriously as part of comprehensive disease management in AD,” Tian continued. “In addition to tracking skin lesions and inflammatory markers, clinicians may also benefit from paying closer attention to stress burden and psychological status in their patients — for example, by incorporating more structured assessment of stress levels into routine evaluation.”

Precision Medicine

Commenting for Medscape Medical News, Mohammad Jafferany, MD, professor of psychodermatology, psychiatry, and behavioral sciences, Covenant HealthCare College of Medicine, Central Michigan University, Saginaw, Michigan, said the study “reinforces that stress is not just psychological, but it directly activates nerves in the skin, recruits inflammatory cells, and worsens disease, highlighting the importance of stress management.”

Jafferany, who serves as the president of the Association for Psychocutaneous Medicine of North America, said the findings could “open the door to precision therapies targeting neuroimmune pathways.” In particular, he added, patients with high eosinophils and stress-triggered flares “may represent a distinct subtype of AD that could benefit from targeted approaches.”

The best management “may combine standard anti-inflammatory therapy; stress reduction techniques like cognitive-behavioral therapy, mindfulness, and sleep optimization; and possibly future neuroimmune-targeted pharmacotherapy,” Jafferany added.

Also asked to comment, Gil Yosipovitch, MD, professor of medical dermatology and director of the Miami Itch Center, University of Miami, Coral Gables, Florida, called the study “groundbreaking.” Importantly, he told Medscape Medical News, “Eosinophils emerge not as bystanders but as key amplifiers of disease. They uniquely correlate with stress severity and are required for stress-induced worsening of dermatitis.” Yosipovitch and Jafferany were not involved with the study.

Yosipovitch said that he believes the finding “represents the strongest mechanistic evidence to date that stress exacerbates eczema through a defined neural-immune circuit, explaining why patients can flare rapidly — even before visible inflammation appears.”

In an accompanying perspective, Nicolas Gaudenzio, PhD, and Lilian Basso, PhD, of the University of Toulouse, Institut National de la Santé et de la Recherche Médicale, Toulouse, France, noted that “a growing body of research highlights the bidirectional communication between the nervous and immune systems.”

It remains “unclear how different types of psychological stress…engage the neuroimmune axis that the authors identified,” they stated. It’s also unknown whether other immune cell types or neuronal subtypes are involved. Further research should investigate these questions as well as the potential existence of similar mechanisms in other “stress-sensitive inflammatory diseases, such as psoriasis or inflammatory bowel disease,” they added.

This work was supported by the National Natural Science Foundation of China, the National Key R&D Program of China, and the Feng Foundation of Biomedical Research. No disclosures were listed for Gaudenzio and Basso. Tian and coauthors declared having no relevant financial relationships. Jafferany has received honoraria/consulting fees from Boehringer Ingelheim and La Roche-Posay and book royalties from American Psychiatric Publishing and Springer Nature publishers. He is the president of the Association for Psychocutaneous Medicine of North America and is a member of the board of directors of the International Society of Dermatology. Yosipovitch reported being an advisory board member of AbbVie, Arcutis, Amgen, Attovia, Boehringer Ingelheim, Celldex, Escient Health, Eli Lilly, Galderma, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, Sanofi, Vifor, GlaxoSmithKline, and Celldex. He reported receiving support from Eli Lilly, LEO Pharma, Novartis, Pfizer, Galderma, Escient, Clexio, Regeneron, Sanofi, Celldex, Kiniksa, Pfizer, and AbbVie.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).