A signaling partnership between two immune molecules, IL-31 and IL-33, is emerging as a key driver of the intense itch that defines atopic dermatitis, helping explain why scratching can rapidly worsen symptoms and why some newer targeted drugs are effective.
Atopic dermatitis is a chronic inflammatory skin disease marked by a weakened skin barrier, dryness, and recurring eczema-like lesions. For many patients, relentless itching is the most disruptive symptom, contributing to broken skin, infections, and significant sleep disturbance. The new review describes how a “cytokine axis” – a reinforcing feedback loop between IL-33 and IL-31 – links immune activation directly to nerve signaling that produces itch.
IL-33 is released by skin cells, particularly keratinocytes, when the skin barrier is injured by irritation, allergens, infection, or mechanical damage such as scratching. In a report in the International Journal of Molecular Sciences, the researchers describe IL-33 as an “alarmin,” a distress signal that alerts the immune system to tissue injury. Once released, IL-33 promotes a type 2 immune response, stimulating immune cells to produce inflammatory mediators including IL-4, IL-5, and IL-13.
This inflammatory environment then increases IL-31, which is produced mainly by type 2 helper T cells, but can also come from mast cells, eosinophils, and other immune cells. IL-31 stands out because it can act directly on itch-sensing nerve fibers in the skin, triggering the sensation of itch and encouraging nerve growth that may heighten skin sensitivity over time. At the same time, IL-31 can worsen barrier weakness by interfering with normal keratinocyte maturation and reducing key structural proteins such as filaggrin.
Together, these effects help create a self-perpetuating itch–scratch cycle: injury causes IL-33 release, IL-33 amplifies type 2 inflammation and IL-31 production, IL-31 drives itch and barrier disruption, and scratching causes further injury and renewed IL-33 release. Studies summarized in the review report that higher IL-31 and IL-33 levels tend to track with disease severity, supporting their clinical relevance.
For clinicians and laboratories tracking therapeutic response, the IL-31/IL-33 axis offers a clearer biological explanation for itch severity – and a potential framework for selecting and monitoring emerging treatments.
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