A breakthrough method for addressing rosacea and other inflammatory skin issues may soon emerge, as highlighted by a study from the University of Pittsburgh published today in Science Translational Medicine.
Researchers discovered that a substance named SYM2081 effectively reduced inflammation-inducing mast cells in experiments involving mice and human skin samples. This discovery opens the door for new topical treatments aimed at alleviating symptoms such as itching and hives linked to skin conditions influenced by mast cells.
“I’m genuinely enthusiastic about the potential applications of this research,” stated Daniel Kaplan, M.D., Ph.D., the senior author and a professor of dermatology and immunology at Pitt. “At present, effective therapies targeting mast cells are limited, which leads us to believe our method could offer significant advantages for various skin disorders, such as rosacea, eczema, hives, and mastocytosis.”
Mast cells contain small packets known as granules that are loaded with histamine and other substances that trigger inflammatory responses. When these cells are activated, the granules burst, releasing compounds that kickstart a range of immune actions. Although this degranulation process is crucial for defense against dangers like bee venom, snake bites, and harmful bacteria, inappropriate mast cell activation can also result in allergic reactions, manifesting as swelling, hives, itching, and in extreme cases, anaphylaxis.
In a previous study published in Cell, Kaplan and his team identified that skin neurons release a neurotransmitter called glutamate, which diminishes mast cell activity. When these neurons were removed or the receptor for glutamate was blocked, mast cells grew excessively active, causing increased inflammation.
“This discovery led us to consider if the opposite approach might yield positive outcomes,” Kaplan noted. “If we stimulate the glutamate receptor, perhaps we can reduce mast cell activity and inflammation.”
To investigate this idea, lead author Youran Zhang, a medical student at Tsinghua University who researched this project as a visiting scholar in Kaplan’s lab, alongside Tina Sumpter, Ph.D., a research assistant professor at the Pitt Department of Dermatology, examined a substance known as SYM2081, or 4-methylglutamate. This compound activates a glutamate receptor known as GluK2, found primarily on mast cells.
They confirmed that SYM2081 effectively reduced both mast cell degranulation and growth in both mouse and human skin models. Furthermore, when mice were treated with a topical cream containing SYM2081 prior to the onset of rosacea- or eczema-like symptoms, they experienced significantly milder skin inflammation and other disease symptoms.
According to Kaplan, these findings indicate that a daily cream featuring a GluK2-activating compound could be a viable strategy for preventing rosacea and other inflammatory skin conditions.
Rosacea is a persistent skin condition that can lead to symptoms resembling acne, broken blood vessels, thickened skin, and facial redness.
“Though there are effective treatments available for various forms of rosacea, many rely on antibiotics and only address certain symptoms,” Kaplan explained. “Currently, there are no satisfactory treatments for facial flushing, making this a critical area of need. Our findings imply that activating GluK2 to suppress mast cells could help lessen the flushing associated with rosacea.”
Having shown the proof-of-concept for their strategy, the researchers aim to develop new GluK2-activating substances that could move into clinical trials. Additionally, they have sought a patent through the Pitt Office of Innovation and Entrepreneurship for using SYM2081 to dampen mast cell function.
Other contributors to the study included 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 associated with Pitt, along with Yufan Yang from Pitt and Tsinghua University.
This research received support from the National Institute for Health (NIH; R01AR071720, R01 AR077341, R01AR079233, R01AR074285, DP2AI164325, U01EY034711, and T32AI089443) and the Pitt Center for Research Computing, funded by the NIH (S10OD028483).
