1/30/2025
PITTSBURGH — 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.
PHOTO DETAILS: click image for high-res version
CAPTION: Daniel Kaplan, M.D., Ph.D.
CREDIT: Nate Langer, UPMC
