It can be a relief to scratch the occasional itch, but when an itch gets out of control and doesn’t stop it can become a serious health problem. Scientists at the University of California, San Francisco (UCSF), now report on the discovery of a feedback loop that is centered on a single immune protein, IL-31, which both causes the urge to itch and dials back nearby inflammation. Previous studies suggested that IL-31 signals itch and promotes skin inflammation. The UCSF team discovered that neurons responding to IL-31 that trigger a scratch also prevent immune cells from overreacting and causing more widespread irritation.
IL-31 is found throughout the body, and findings from the newly reported study in mouse models represent what the researchers suggest is a breakthrough that could transform how doctors treat conditions from eczema, asthma, and allergies, as well as Crohn’s and other inflammatory diseases. The results could lay the groundwork for a new generation of drugs that interact more intelligently with the body’s innate ability to self-regulate.
“We tend to think that immune proteins like IL-31 help immune cells talk to one another, but here, when IL-31 talks to neurons, the neurons talk right back,” said Marlys Fassett, MD, PhD, UCSF professor of dermatology. “It’s the first time we’ve seen the nervous system directly tamp down an allergic response.” Added Mark Ansel, PhD, UCSF professor of immunology, “IL-31 causes itch in the skin, but it’s also in the lung and in the gut … We now have a new lead for fighting the many diseases involving both the immune and nervous systems.” Fassett is lead author, and Ansel is senior author of the team’s published paper in Science Immunology, titled “IL-31–dependent neurogenic inflammation restrains cutaneous type 2 immune cell accumulation and cytokine production in allergic dermatitis.”
IL-31 is one of several “itch cytokines” that has the ability to instigate itch in animals and people. Administering IL-31 to animals triggers acute-onset itching, and mice engineered to overexpress the IL-31 gene in immune system T cells develop a serious spontaneous itch, the authors noted. “Transgenic mice that constitutively overexpress Il31 in T cells (IL31Tg) develop spontaneous itch so severe that they develop scratching-induced skin lesions …”
In contrast, scratching in animal models of induced dermatitis is ameliorated in individuals lacking the Il31 gene, “… confirming that IL31 is necessary for contact hypersensitivity-associated itch …” the team stated. However, they further noted, “Whereas IL-31–dependent itch-sensory pathways have been well characterized, the contributions of IL-31 to cutaneous inflammation remain unclear.”
For their reported study Fassett, a dermatologist and a researcher, teamed up with Ansel, a former colleague and asthma expert. The researchers removed the IL-31 gene from mice and exposed the animals to the house dust mite (HDM), a common, itchy allergen. “We wanted to mimic what was actually happening in people who are chronically exposed to environmental allergens,” Fassett said. “As we expected, the dust mite didn’t cause itching in the absence of IL-31, but we were surprised to see that inflammation went up.”
Why was there inflammation but no itching? Fassett and Ansel found that a cadre of immune cells had been called into action in the absence of the itch cytokine. Without IL-31, the body was effectively blindly waging an immunological war.
Ansel and Fassett then homed in on the nerve cells in the skin to which IL-31 signal and discovered that the same nerve cells that spurred a scratch also dampened any subsequent immune response. These nerve cells were integral to keeping inflammation in check, but without IL-31, they let the immune system run wild.
Fassett and Ansel also found that these neurons released a neuropeptide called calcitonin gene-related protein (CGRP), in response to the IL-31 itch signal, which could be responsible for dampening the immune response. The experiments in mice with chronic atopic dermatitis (AD)-like symptoms indicated that CGRP ultimately restrains the activity of T cells lurking in the skin that cause surface-level inflammation. Corroborating these results, the team demonstrated that mice without IL-31 receptors showed more severe type 2 immuno-inflammatory responses to allergen exposures. “ … we demonstrate that IL-31 activates sensory neuron–mediated pathways of dual purpose in allergic dermatitis: to induce itch and to stimulate neurogenic inflammation via CGRP release,” they wrote.
The findings match with what dermatologists were increasingly seeing with a new IL-31-blocking drug, nemolizumab, which has been developed to treat eczema. “Given the translational relevance of these conclusions to clinical dermatology, we note similar results from anti-IL31RA (nemolizumab) clinical trials for AD,” the authors pointed out. While clinical trial patients using the drug found that the dry, patchy skin of their eczema receded they also sometimes demonstrated flare-ups of other skin irritation, and even inflammation in the lungs. “Nemolizumab-treated AD patients experienced rapid improvement in pruritus but delayed improvements in dermatitis metrics, paradoxical dermatitis flares, and dose-dependent asthma exacerbations.”
Ansel commented, “When you give a drug that blocks the IL-31 receptor throughout the whole body, now you’re changing that feedback system, releasing the brakes on allergic reactions everywhere.” Fassett added, “The idea that our nerves contribute to allergy in different tissues is game changing … If we can develop drugs that work around these systems, we can really help those patients that get worse flares after treatment for itch.”
The team concluded, “Together, these results illustrate a previously unrecognized neuroimmune pathway that constrains type 2 tissue inflammation in the setting of chronic cutaneous allergen exposure, and may explain paradoxical dermatitis flares in atopic patients treated with anti-IL31RA therapy.”
Fassett recently founded her own lab at UCSF to tease apart these paradoxes in biology that complicate good outcomes in the clinic. And Ansel is now interested in what this itch cytokine is doing beyond the skin. “You don’t itch in your lungs, so the question is, what is IL-31 doing there, or in the gut?” Ansel asked. “But it does seem to have an effect on allergic inflammation in the lung. There’s a lot of science ahead for us, with immense potential to improve therapies.”
