Scratching neurons: A potential itch solution?

IL-31 limits allergic dermatitis immune response.

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Sometimes, scratching an itch feels good, but if it gets too intense, it can lead to health issues. So, how does the body know when to stop itching?

Researchers at University of California-San Francisco are getting closer to an answer. They’ve made a significant discovery involving a particular immune protein called IL-31. This protein triggers the desire to scratch and helps reduce inflammation nearby. This breakthrough could change the way doctors treat conditions like eczema and allergies.

Published on October 13, 2023, in Science Immunology, these discoveries set the stage for more competent medicines that work in harmony with the body’s self-regulation.

Before, people thought IL-31 made you itch and caused skin inflammation. However, the UCSF team found that the nerve cells responding to IL-31 make you scratch. However, they also stop immune cells from going overboard and causing more irritation everywhere.

Marlys Fassett, MD, Ph.D., UCSF professor of dermatology and lead author of the study, said, “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. It’s our first time seeing the nervous system directly tamp down an allergic response.”

This discovery might change how we treat diseases like asthma and Crohn’s that cause inflammation because IL-31 is found all over the body.

Dr. Mark Ansel, a UCSF professor, explained, “IL-31 makes your skin itch, but it’s also in your lungs and gut. This finding gives us a new path to tackle diseases that affect both the immune and nervous systems.”

IL-31 is an ‘itch cytokine’ because it can trigger itching in animals and humans. Dr. Fassett, a dermatologist and researcher, has been curious about this since joining UCSF in 2012, a few years after its discovery. She teamed up with Dr. Ansel, an asthma expert, to investigate.

To understand its role, they removed the IL-31 gene from mice and exposed them to a common allergen, house dust mites, which often cause itching.

What they discovered was unexpected. Without IL-31, the mice didn’t itch, but they did experience more inflammation. It turned out that the absence of IL-31 led to the activation of a group of immune cells. Without the ‘itch cytokine,’ the body unknowingly triggered an immune response.

Ansel and Fassett then focused on the skin neurons receiving IL-31 signals. They found that these same neurons, which triggered scratching, also controlled the immune response. These neurons play a crucial role in keeping inflammation under control. However, in the absence of IL-31, the immune system became unregulated.

Their findings align with dermatologists’ observation of a new drug called nemolizumab, which blocked IL-31 and was designed for eczema treatment. While patients in clinical trials saw improved eczema, some experienced other skin irritations and even lung inflammation when on the drug.

“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,” Ansel said.

Fassett and Ansel also found that these neurons released their signal, called CGRP, in response to the itch signal, which could be responsible for dampening the immune response.

“The idea that our nerves contribute to allergy in different tissues is game-changing,” Fassett said. “If we can develop drugs that work around these systems, we can help those patients that get worse flares after treatment for itch.”

Fassett recently founded her 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.

Ansel asked, “You don’t itch in your lungs, so the question is, what is IL-31 doing there, or in the gut?“However, it does seem to affect allergic inflammation in the lungs. There’s much science ahead for us, with immense potential to improve therapies.”

In conclusion, this study highlights the intricate interplay between neurons, immune responses, and the sensation of itching, shedding light on the dual role of IL-31 in promoting scratching and regulating inflammation. These findings have significant implications for developing drugs that can intelligently interact with these systems, potentially offering more effective treatments for individuals struggling with chronic itching and related conditions.

Journal Reference:

  1. Marlys S. Fassett, Joao M. Braz et al., IL-31–dependent neurogenic inflammation restrains cutaneous type 2 immune response in allergic dermatitis. Science Immunology. DOI: 10.1126/sciimmunol.abi6887.

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