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In Type 2 Inflammation, an Unexpected Relationship Between Itchiness and Inflammation


When interleukin (IL)-31 stimulates nerves that create itchiness it may also have a downstream effect that tempers inflammatory processes, according to mouse model research done by investigators at the University of California, San Francisco.

P© Andrew Popov  stock.adobe.com

P© Andrew Popov stock.adobe.com

The excessive type 2 inflammation is the underlying cause of many cases of asthma and atopic dermatitis and also several lesser known conditions such as chronic rhinosinusitis with nasal polyps and eosinophilic esophagitis. It is a complex process that activates a cascading menagerie of cells of the immune system and those related to it. An integral part of that process is the swarm of cytokines that gets set loose, including interleukin (IL)-4, IL-5 and IL-13.

A growing number of treatments designed to quell type 2 inflammation do so by inhibiting those interleukins. Dupixent (dupilumab), for example, works by inhibiting the activity of IL-4 and IL-13.

This understanding of type 2 inflammation — and the success of cytokine-targeted treatments — have led to a surge of research into cytokines and the role they play in inflammation.

A research article reported in the Journal Science Immunology earlier this month profiled IL-31, one of most intriguing cytokines in type 2 inflammation. First author Marlys S. Fassett, M.D., Ph.D., of the University of California, San Francisco, and her colleagues explained that IL-31 sports a heterodimeric receptor that latches on to sensory neurons that activate the itching sensation. But its role in type 2 inflammation, particularly in the skin, has been difficult to decipher, partly because the scratching caused by the itching results in skin injury that makes it difficult to sort out cause and effect. It has also been difficult to square research results, with some findings suggesting that IL-31 revs up type 2 inflammation, suggesting that it has the opposite effect of calming it down.

Marlys S. Fassett, M.D., Ph.D.

Marlys S. Fassett, M.D., Ph.D.

Fassett and her colleagues set out to shed some light on these seemingly incompatible findings and other unanswered questions about IL-31 by conducting experiments with mice genetically engineered to lack IL-31 and drawing comparisons to normal mice. The researchers spread an ointment containing allergens extracted from house dust mites on areas of shaved skin to create an experimental version of skin allergy and type 2 inflammation. Then they conducted a battery of tests of skin and nerve tissue and of cytokine levels in serum to assess the differences between mice without the IL-31 cytokine and those with it that would then allow them to draw some inferences about the role of IL-31 in type 2 inflammation.

What they found was evidence of a fascinating interplay between the neuronal and inflammatory systems and for IL-31 having a complicated role as a regulator of type 2 inflammation rather than simply promoting it.

According to their findings, IL-31 has a moderating effect on inflammation through its interaction with afferent nerves. Measurements by Fassett and her colleagues showed that IL-31 not only produces the itching sensation by stimulating those nerves but also induces the release of calcitonin gene-related protein (CGRP). They then showed that CGRP isn’t just a by-stander to the inflammatory processes that IL-31 is party to but an active influencer of them by direct blunting the effect of CD4+ T cells in the skin. This limits their proliferation and their production of IL-31 cytokines.

In other words, the itching that IL-31 causes also starts a cascade of signaling that reins in the inflammatory processes. Their results also suggest that it is just a subset of sensory nerves that respond to IL-31 and have a moderating effect on inflammation by secreting CGRP.

“The capacity of IL-31 to incite CGRP release from sensory affects is unexpected” and is relevant to the understanding of type 2 inflammatory disease and possible treatments, wrote Fassett and her colleagues. They note that their findings about IL-31’s governing effect on type 2 inflammation are consistent with clinical trial results for nemolizumab, an IL-31 inhibitor that is an experimental treatment for prurigo nodularis. Patients treated with the nemolizumab experienced rapid improvement in pruritus, but the drug’s effects on dermatitis were delayed and, in some patients, dermatitis flared up.

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