Delving deeper: Rosacea peptide research focuses on cathelicidins

November 1, 2008

Cathelicidins appear to have dual roles in the skin, working not just as antimicrobials that act as natural antibiotics but also as proponents of healing. Researchers are looking into the underlying workings of antimicrobial cathelicidins with the hope of better understanding their role in osacea. Factors such as toll-like receptors and vitamin D3 appear to be part of the equation.

Key Points

Several groundbreaking studies from the University of California, San Diego, have noted that cathelicidins appear to play dual roles in the skin - functioning not only as antimicrobials that act as natural antibiotics but also acting as proponents of healing.

In the latter role, cell-signaling molecules initiate a host response that results in cytokine release, inflammation, angiogenesis and re-epithelialization.

Interestingly, people with rosacea have been found to have an overexpression of cathelicidins, which, combined with the generation of increased serine protease activity, is blamed for causing the clinical characteristics of rosacea (Nat Med. 2007 Aug;13(8):975-980).

The bigger question, however, has been why cathelicidins are over-produced in people with rosacea, and researchers are making some progress in finding answers.

"We showed that people with rosacea have abnormal enzymes and abnormally high expression of cathelicidins, and those factors were leading to the disease, but we didn't know why this was occurring," says Richard Gallo, M.D., Ph.D., professor of medicine and chief of the division of dermatology, University of California, San Diego, School of Medicine and the dermatology section of the Veterans Affairs San Diego Healthcare System.

"Now, we are focusing on trying to understand the regulation of the cathelicidins and enzymes and better explain why individuals with rosacea have that abnormal response," he says.

Toll-like receptors

Ongoing research has further confirmed the original findings about cathelicidins, showing how the innate immune system is key in the manifestation of rosacea. But it has also led to interest in another possible piece of the puzzle - toll-like receptors.

"We're learning that certain pattern receptors - toll-like receptors - seem to also be abnormal in rosacea patients," Dr. Gallo says.

Toll-like receptors are one of several systems that the skin uses to detect changes in the environment. A problem with TLRs could, therefore, explain the increased sensitivity of patients with rosacea.

Vitamin D3

Vitamin D3 has also been a focus of cathelicidin research, with recent studies showing that vitamin D plays a major role in the regulation of cathelicidin expression (Exp Dermatol. 2008 Aug;17(8):633-639).

"We know that too much vitamin D will drive the same types of problems that people with rosacea have, and there are certain families with bad rosacea that actually have a mutation in the vitamin D receptor, so we think there's a strong link," Dr. Gallo tells Dermatology Times.

"We don't know if it's a matter of too much oral vitamin D or whether people are perhaps too sensitive to the vitamin," he adds.

Atopic dermatitis

Vitamin D has also been found to play an intriguing role in atopic dermatitis (AD), which could, in turn, shed some light on its function in rosacea.

Patients with AD have been shown to have the opposite problem seen in rosacea patients - they have a suppression of cathelicidins, and researchers suggest that this may explain why people with AD are susceptible to infections.

Dr. Gallo recently conducted a clinical study to get a better understanding of the role of vitamin D in people with AD.

"When we learned that vitamin D will increase the antimicrobial peptides like cathelicidins, we did a clinical study to look at what the effect of oral administration of vitamin D in AD patients would be.

"What we found was that oral supplementation with vitamin D did indeed improve the ability of atopic dermatitis patients to produce cathelicidin, so there is an indication that the vitamin could eventually lead to atopic dermatitis patients' ability to resist infection."

The study wasn't designed to look at the clinical manifestation of the condition - that will come in the future, Dr. Gallo says.

The findings also raise the question that if vitamin D supplementation can help boost the levels of cathelicidins in people with AD, could therapies targeting the vitamin D3 pathway somehow conversely reduce the levels in rosacea patients? That's something Dr. Gallo is also exploring in current research.

"We are working on the opposite approach with rosacea patients, which is to try to therapeutically decrease their levels of cathelicidins," he says. "There are some candidate drugs we are looking at, but we haven't started the trials yet."

Disclosure: Dr. Gallo reports no relevant disclosures.

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