Feeling itchy? Study suggests novel way to treat inflammatory skin conditions

The researchers found that a compound called SYM2081 inhibited inflammation-driving mast cells in mouse models and human skin samples, paving the way for new topical treatments to prevent itching, hives and other symptoms of skin conditions driven by mast cells.

“I’m really excited about the clinical possibilities of this research,” said senior author Daniel Kaplan, M.D., Ph.D., professor of dermatology and immunology at Pitt. “Currently, there aren’t a lot of good therapies that target mast cells, so we think that our approach could potentially have huge benefits in many skin conditions, including rosacea, eczema, urticaria and mastocytosis.”

Mast cells are filled with tiny packages, or granules, each brimming with histamine and other compounds that act as signals or activators of inflammatory pathways. When mast cells are activated, the packages spill open, releasing compounds that trigger a suite of immune responses. This process, known as degranulation, is essential for protection against threats such as bee venom, snake bites and pathogenic bacteria, but erroneous activation of mast cells also triggers allergic reactions, including swelling, hives, itching and, in severe cases, anaphylaxis.

In a previous Cellpaper, Kaplan and his team found that neurons in the skin release a neurotransmitter called glutamate that suppresses mast cells. When they deleted these neurons or inhibited the receptor that recognizes glutamate, mast cells became hyperactive, leading to more inflammation.

“This finding led us to wonder if doing the opposite would have a beneficial effect,” said Kaplan. “If we activate the glutamate receptor, maybe we can suppress mast cell activity and inflammation.”

To test this hypothesis, lead author Youran Zhang, a medical student at Tsinghua University who did this research as a visiting scholar in Kaplan’s lab, and Tina Sumpter, Ph.D., a research assistant professor in the Pitt Department of Dermatology, looked at a compound called SYM2081, or 4-methylglutamate, that activates a glutamate receptor called GluK2 found almost exclusively on mast cells.

Sure enough, they found that SYM2081 effectively suppressed mast cell degranulation and proliferation in both mice and human skin samples. And when the mice received a topical cream containing SYM2081 before the induction of rosacea- or eczema-like symptoms, skin inflammation and other symptoms of disease were much milder.

According to Kaplan, these findings suggest that suppressing mast cells with a daily cream containing a GluK2-activating compound could be a promising way to prevent rosacea and other inflammatory skin conditions.

Rosacea is a chronic skin condition that may cause acne-like pimples, broken blood vessels, skin thickening and facial flushing.

“Although there are excellent therapies available for different types of rosacea, many are antibiotic-based and they only target some of the symptoms,” said Kaplan. “There are no good therapies for flushing, so this is a significant unmet need. Our study suggests that suppressing mast cells by activating GluK2 could reduce the flushing associated with rosacea.”

Now that the researchers have demonstrated proof-of-concept of their approach, they hope to engineer new GluK2-activating compounds that could eventually be tested in clinical trials. Through the Pitt Office of Innovation and Entrepreneurship’s Innovation Institute, they have also applied for a patent for the use of SYM2081 to suppress mast cell function.

Other authors on the study were Swapnil Keshari, Kazuo Kurihara, M.D., Ph.D., James Liu, Lindsay M. McKendrick, Chien-Sin Chen, Ph.D., Louis D. Falo Jr., M.D., Ph.D., and Jishnu Das, Ph.D., all of Pitt; and Yufan Yang, of Pitt and Tsinghua University.

This work was supported by the National Institute for Health (NIH; R01AR071720, R01 AR077341, R01AR079233, R01AR074285, DP2AI164325, U01EY034711 and T32AI089443) and the Pitt Center for Research Computing, which is supported by the NIH (S10OD028483).