Photo courtesy Morguefile.com
Finding may represent the possibility of disease control without immune suppression
The small skin protein Rac1, involved in wound repair, appears to link known environmental triggers of psoriasis to genetic predisposition to the condition and may represent a new drug target. That’s according to recent research from the Stanford University School of Medicine in California, published online in Journal of Clinical Investigation (June 13, 2016).
Because of the inherent limitations with long-term immune suppression as a therapy for psoriasis, the authors were investigating other options for patients by studying the skin’s role in the disease process. That included considering environmental triggers, which led them to look at Rac1 and its role in both wound repair and in strep infection.
“Both of these processes activate a small protein called Rac1,” said Dr. Peter Marinkovich, associate professor of dermatology at Stanford University School of Medicine and senior author of the paper, in a press release. “So we wondered if Rac1 was somehow involved in triggering psoriasis in susceptible people.”
According to the release, activated Rac1 is believed to promote epidermal cell proliferation, as well as sending signals to activate the immune system as part of the normal wound healing response. Some psoriasis-linked mutations also affect molecules in the same signaling pathway as Rac1.
Skin biopsies from 20 people with psoriasis consistently had highly activated Rac1, according to the paper, and artificially activating Rac1 in a mouse model produced psoriatic symptoms.
“They had scaling of the skin and arthritis in their joints that precisely mimics what we’ve seen in the clinic,” Dr. Marinkovich said. However, mice engineered to lack immune T cells did not develop psoriatic symptoms, further confirming the immune system’s role in the disorder.
Further, when Rac1 activity was blocked in human psoriatic skin patches transplanted onto mice, skin hyperplasia reversed and cytokine recruitment into the skin patch decreased.
“Psoriasis is one of the most prevalent skin diseases in the world,” said Dr. Marinkovich. “But it’s been difficult to study due to the complex interplay between genetic and environmental influences. Now we’ve learned that targeting Rac1 activation in the skin, rather than the immune system’s role in the disease, may be a way to treat the disease without needing to suppress the immune system.”
“The study is the first to find a molecule linking genetic susceptibility to the disease with the environmental causes known to trigger it,” Dr. Marinkovich said. “We’d like to understand all the steps between these gene defects and Rac1 activation. Then we can try to identify drugs that can down-regulate the cause of abnormal Rac1 activation in psoriasis. The availability of a cream or other topical application could completely change the way we treat psoriasis in the clinic.”