Scratching an itch promotes antibacterial inflammation
Summary author: Walter Beckwith
American Association for the Advancement of Science (AAAS)
New research uncovers the dual nature of scratching an itch; although it can worsen skin inflammation, it can also boost immune defenses against bacterial infections at the injury site. The findings shed light on a pharmacologically targetable pathway that explains how scratching triggers inflammation, resolving the paradox of scratching as both a harmful pathological process and a beneficial evolutionary adaptation. Scratching is a natural, instinctive response to the sensation of itching, and it plays a central role in many skin conditions and injuries, such as dermatitis and insect bites, where chronic itching can be a major source of discomfort. Scratching can aggravate the condition by promoting inflammation in a self-perpetuating "itch-scratch cycle," where the scratching intensifies the itch and can exacerbate the injury. Yet unlike pain, which typically causes an aversion response, scratching can feel pleasurable, which suggests it might serve some adaptive benefit. However, the mechanisms by which scratching contributes to skin inflammation and whether the itch-scratch reflex offers any benefits to the host remain poorly understood. Using a novel genetically modified mouse model, Andrew Liu and colleagues explored how eliminating the function of itch-sensing neurons called nonpeptidergic 2 (NP2) affects the connection between itch, scratch and inflammation. Liu et al. discovered that scratching activates pain-sensing neurons that release substance P (SP), which stimulates mast cells to increase inflammation, mainly by attracting neutrophils. However, while scratching can aggravate issues like dermatitis, it may also help host immune defense by reducing bacteria, such as Staphylococcus aureus, during infections. Moreover, scratching can influence the skin's microbiome at the injury site, potentially preventing microbiota imbalances, although chronic conditions like atopic dermatitis complicate this. According to the authors, the findings suggest that scratching serves both as a pathological driver of inflammation and an evolutionary mechanism to bolster protection against infection. “Beyond defining a previously unidentified neuroimmune itch-scratch circuit, the findings of Liu et al. may lay a foundation for discoveries to help people suffering from chronic itch,” writes Aaron Ver Heul in a related Perspective.
Podcast: A segment of Science's weekly podcast with Daniel Kaplan, related to this research, will be available on the Science.org podcast landing page after the embargo lifts. Reporters are free to make use of the segments for broadcast purposes and/or quote from them – with appropriate attribution (i.e., cite "Science podcast"). Please note that the file itself should not be posted to any other Web site.
Journal
Science
Article Title
Scratching promotes allergic inflammation and host defense via neurogenic mast cell activation
Article Publication Date
31-Jan-2025
Why you shouldn’t scratch an itchy rash: New study explains
University of Pittsburgh
image:
Daniel Kaplan, M.D., Ph.D., professor of dermatology and immunology at the University of Pittsburgh
view moreCredit: Nate Langer, UPMC
Your parents were right: Scratching an itchy rash really does make it worse. Now we know why, thanks to new research published today in the journal Science that uncovers how scratching aggravates inflammation and swelling in a mouse model of a type of eczema called allergic contact dermatitis.
“At first, these findings seemed to introduce a paradox: If scratching an itch is bad for us, why does it feel so good?” said senior author Daniel Kaplan, M.D., Ph.D., professor of dermatology and immunology at the University of Pittsburgh. “Scratching is often pleasurable, which suggests that, in order to have evolved, this behavior must provide some kind of benefit. Our study helps resolve this paradox by providing evidence that scratching also provides defense against bacterial skin infections.”
Allergic contact dermatitis is an allergic reaction to allergens or skin irritants — including poison ivy and certain metals such as nickel — leading to an itchy, swollen rash. Succumbing to the often-irresistible urge to scratch triggers further inflammation that worsens symptoms and slows healing.
To figure out what drives this vicious cycle, Kaplan, first author Andrew Liu, student in Pitt’s Medical Scientist Training Program, and their team used itch-inducing allergens to induce eczema-like symptoms on the ears of normal mice and those that don’t get itchy because they lack an itch-sensing neuron.
When normal mice were allowed to scratch, their ears became swollen and filled with inflammatory immune cells called neutrophils. In contrast, inflammation and swelling were much milder in normal mice that couldn’t scratch because they wore tiny Elizabethan collars, similar to a “cone of shame” that a dog might sport after a visit to the vet, and in animals that lacked the itch-sensing neuron. This experiment confirmed that scratching further aggravates the skin.
Next, the researchers showed that scratching causes pain-sensing neurons to release a compound called substance P. In turn, substance P activates mast cells, which are key coordinators of inflammation that drive itchiness and inflammation via recruitment of neutrophils.
“In contact dermatitis, mast cells are directly activated by allergens, which drives minor inflammation and itchiness,” explained Kaplan. “In response to scratching, the release of substance P activates mast cells through a second pathway, so the reason that scratching triggers more inflammation in the skin is because mast cells have been synergistically activated through two pathways.”
Mast cells are culprits in a range of inflammatory skin conditions and allergic reactions, but they’re also important for protecting against bacteria and other pathogens. As such, the researchers wondered if scratching-induced activation of mast cells could affect the skin microbiome.
In experiments led by coauthor Marlies Meisel, Ph.D., assistant professor of immunology at Pitt, the team showed that scratching reduced the amount of Staphylococcus aureus, the most common bacteria involved in skin infections, on the skin.
“The finding that scratching improves defense against Staphylococcus aureus suggests that it could be beneficial in some contexts,” said Kaplan. “But the damage that scratching does to the skin probably outweighs this benefit when itching is chronic.”
Now, the researchers are investigating new therapies for dermatitis and other inflammatory skin conditions such as rosacea and urticaria that suppress inflammation by targeting receptors on mast cells.
Other researchers on the study were Youran Zhang, Chien-Sin Chen, Ph.D., Tara N. Edwards, Ph.D., Torben Ramcke, M.D., Lindsay M. McKendrick, Eric S. Weiss, Jacob E. Gillis, Colin R. Laughlin, Simran K. Randhawa, Catherine M. Phelps, Kazuo Kurihara, M.D., Ph.D., Hannah M. Kang, Sydney-Lam N. Nguyen, Jiwon Kim, Tayler D. Sheahan, Ph.D., Sarah E. Ross, Ph.D., and Tina L. Sumpter, Ph.D., all of Pitt and UPMC; and Sumeyye Ozyaman, of Pitt and Istanbul Medipol University.
This research was supported by the National Institutes of Health (T32NS73548, T32CA0820840, R01DK130897, U24EY035102, K99NS126569, R01AR071720 and R01AR077341) and the German Research Foundation.
Journal
Science
Article Title
Scratching promotes allergic inflammation and host defense via neurogenic mast cell activation
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