The body uses molecular messengers, known as cytokines, to manage communication between immune cells and other systems, including the nervous system. Interleukin-31 (IL-31) is a specific cytokine that is a major factor in the persistence of skin inflammation and intense itching (pruritus). Its discovery was a breakthrough in understanding why certain chronic skin conditions cause relentless itch that traditional antihistamines often fail to relieve. IL-31 illuminates a direct link between the immune system and the sensory nerves that transmit the itch signal.
The Molecular Identity of IL-31
Interleukin-31 is classified as a member of the IL-6 cytokine family. This molecule is primarily produced by activated T-helper 2 (Th2) cells, a subset of white blood cells that orchestrates the immune response against pathogens and allergens. Other immune cells, including mast cells, macrophages, and dendritic cells, also contribute to IL-31 production in inflamed tissue.
IL-31 exerts its biological effects by binding to a dedicated receptor complex on the surface of target cells. This complex is a heterodimer, formed by two different protein subunits: the Interleukin-31 Receptor A (IL-31RA) and the Oncostatin M Receptor \(\beta\) (OSMR\(\beta\)). The expression of this unique receptor complex allows IL-31 to send messages directly from the immune system to the nervous system and other skin cells.
How IL-31 Causes Chronic Itching
The primary mechanism by which IL-31 drives chronic pruritus is through its direct interaction with sensory neurons that innervate the skin. The IL-31 receptor complex is expressed on the nerve endings of small-diameter sensory nerve fibers, specifically the unmyelinated C-fibers, which transmit pain and itch sensations. When IL-31, secreted by immune cells, reaches these nerve endings, it binds to the IL-31RA/OSMR\(\beta\) complex, initiating internal signals.
This binding activates intracellular signaling pathways, such as the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway. This effectively transmits an electrical signal up the nerve toward the spinal cord and brain, resulting in the perception of intense itching. This itch is distinctly non-histaminergic, meaning it is not blocked by common antihistamine medications.
The presence of IL-31 also promotes the elongation and branching of these sensory nerve fibers within the skin, potentially leading to a denser network of itch-sensing nerves. This increased nerve density contributes to enhanced sensitivity, making the skin hyper-responsive to minimal stimuli and resulting in the sustained, chronic nature of the itch.
Clinical Relevance in Inflammatory Skin Disease
Elevated levels of IL-31 are associated with the severity of itching in several inflammatory skin conditions. In Atopic Dermatitis (eczema), the concentration of IL-31 in the blood and affected skin tissue correlates directly with the patient’s reported itch intensity. This cytokine is recognized as a central factor in the disease pathology, contributing to the patient’s discomfort.
Another condition, prurigo nodularis, characterized by thick, intensely itchy skin nodules, also shows high levels of IL-31 and its receptor in the lesional skin. Furthermore, IL-31 is implicated in systemic pruritic disorders, such as the chronic itching associated with advanced kidney disease.
Itching caused by IL-31 leads to scratching, which damages the skin barrier and releases inflammatory mediators. The resulting inflammation stimulates immune cells to produce more IL-31, establishing a self-perpetuating “itch-scratch cycle.”
Targeting IL-31 for Treatment
The understanding of IL-31’s role as a direct mediator of chronic itch has paved the way for specific therapeutic strategies. By targeting this molecule or its receptor, researchers aim to silence the persistent itch signal at its source without the systemic effects of traditional immunosuppressants. The most successful approach involves monoclonal antibodies, which are engineered proteins designed to neutralize a specific biological target.
One such therapy is a humanized monoclonal antibody that specifically targets and blocks the IL-31RA subunit of the receptor complex. By preventing IL-31 from binding to its receptor on the sensory neurons, this treatment interrupts the signal transmission that causes chronic pruritus.
Clinical trials have demonstrated that this targeted blockade rapidly reduces the intensity of itching in patients with Atopic Dermatitis and prurigo nodularis. Interrupting the itch-scratch cycle provides symptomatic relief and allows the skin to heal, leading to improvement in the patient’s quality of life and sleep.