Interleukin-31 (IL-31) is a protein that functions as a messenger molecule, known as a cytokine, for communication between cells. As part of the immune system’s network, IL-31 has become a focus for researchers studying inflammatory and allergic conditions since its identification in 2004. It is now understood to be a primary driver of itch and belongs to the IL-6 superfamily of cytokines.
The Function of IL-31 in the Body
IL-31 is primarily produced by Type 2 T helper (Th2) cells, which are activated by stimuli like allergens. Once released, IL-31 interacts with its specific receptor, a complex made of two parts: IL-31 receptor A (IL31RA) and oncostatin M receptor beta (OSMRβ). This receptor is found on several cell types, most notably on sensory nerve cells in the skin.
The primary function of IL-31 is the direct stimulation of these sensory neurons. When IL-31 binds to its receptor on a nerve ending, it triggers an internal signaling cascade involving proteins like Janus kinases (JAKs). This process sends a message to the brain, which interprets it as itch. This mechanism often results in a later-onset but more persistent sensation compared to histamine-induced itch.
Beyond its action on nerves, IL-31 also influences the skin environment by interacting with keratinocytes, the main cells of the epidermis. This interaction can disrupt skin cell differentiation and reduce the production of proteins that maintain the skin barrier, like filaggrin. A compromised skin barrier can lead to increased water loss and make the skin more susceptible to irritants and allergens.
IL-31 also contributes to skin inflammation by promoting the release of other pro-inflammatory molecules. It encourages the growth of sensory nerve fibers, which can increase the skin’s sensitivity to minor stimuli and lead to more sustained itching. The combination of direct nerve stimulation, skin barrier disruption, and inflammatory signaling makes IL-31 a multifaceted molecule.
IL-31’s Role in Medical Conditions
Elevated levels of IL-31 are associated with several chronic inflammatory skin conditions characterized by intense itch (pruritus). The most prominent of these is atopic dermatitis, a common form of eczema. In individuals with atopic dermatitis, IL-31 levels are often higher and correlate with the severity of the disease and the itch.
The itch driven by IL-31 initiates the “itch-scratch cycle” in atopic dermatitis. IL-31 sends the itch signal from the skin to the brain, compelling the person to scratch. Scratching provides temporary relief but damages the skin, weakening the barrier and triggering more inflammation. This response leads to the release of more IL-31, which intensifies the itch and perpetuates the cycle.
IL-31’s involvement extends to other pruritic skin diseases. In prurigo nodularis, a condition with hard, intensely itchy nodules, IL-31 is found at elevated levels and drives the severe itch. IL-31 is also implicated in conditions like chronic spontaneous urticaria and some forms of cutaneous T-cell lymphoma where itch is a major symptom.
Therapeutic Targeting of IL-31
The connection between IL-31 and chronic itch has led to therapies that counteract its effects by targeting its signaling pathway. These treatments offer new options for patients with conditions like atopic dermatitis and prurigo nodularis. The strategies fall into two main categories based on their mechanism of action.
One approach involves monoclonal antibodies, which are lab-produced molecules engineered to target specific substances. An antibody called nemolizumab is designed to bind directly to the IL-31 receptor A (IL31RA). By blocking this part of the receptor, the antibody prevents IL-31 from activating the nerve cell, stopping the itch signal before it can be sent to the brain and leading to rapid relief.
Another strategy uses Janus kinase (JAK) inhibitors. These are small molecule drugs that work inside the cell, unlike monoclonal antibodies which work outside. After IL-31 binds to its receptor, it triggers an internal signaling process that relies on JAK proteins to relay the message.
JAK inhibitors disrupt this intracellular pathway by inhibiting specific JAK proteins, like JAK1 and JAK2. This action blocks the transmission of the itch signal from the receptor to the cell’s nucleus. This interruption prevents the cellular responses that cause itch and inflammation, even if IL-31 is bound to its receptor.