Abnormal peptide expression, enzyme levels linked to acne rosacea
November 1, 2007
Dermatologists are all too familiar with the clinical manifestations of acne rosacea, yet, until now, little has been known about the etiology of the disease. Research out of the University of California, San Diego, offers important new clues.
The culprit - or at least a big potential role-player - appears to be the expression and processing of antimicrobial cathelicidin peptides, which researchers have previously shown to play an important role as a cutaneous defense mechanism.
In taking skin biopsies from patients with rosacea and comparing them with samples of normal skin, researchers found their evidence. Abundant levels of cathelicidins were seen in the rosacea skin, whereas the normal skin had only minimal expression of the peptides.
"We hypothesized that there is a problem in the innate immune system in the skin of patients with rosacea, and we indeed discovered two steps that were wrong in all of the patients we looked at," says Richard L. Gallo, M.D., Ph.D., professor of medicine and chief of the division of dermatology at the University of California, San Diego, School of Medicine and the dermatology section of the Veterans Affairs San Diego Healthcare System.
"The first step was that the rosacea patients produced too much cathelicidin, and the next was that an enzyme in the skin that is responsible for making the cathelicidin into an active form, SCTE, was abnormally produced in rosacea patients," he tells Dermatology Times.
The researchers suspected that cathelicidin played a role in rosacea upon observing that the peptides may have a dual role in immunity by not just killing microbes, but also triggering host tissue responses; hence, they are referred to as "alarmins."
Those responses include the ability to signal an inflammatory reaction and stimulate cytokine release, angiogenesis and the expression of extracellular matrix components.
Testing the hypothesis
Since many of those effects resemble those seen in rosacea, researchers decided to test the theory in a murine model.
They injected cathelicidins found in rosacea in mice or added the protease SCTE. They also studied how protease activity was increased by the targeted deletion of the serine protease inhibitor gene Spink5. Researchers found that each of the processes increased inflammation in mouse skin.
"By taking those peptides and putting them in mice, we were able to reproduce elements of the disease in mouse skin, and support the theory," Dr. Gallo says.
The findings are significant on their own, but they also offer clues to what may be a much bigger picture in the rosacea etiology. The increase in local antimicrobial peptide expression, for instance, may also influence a change in the population of commensal microbes on involved skin. That kind of change in the microflora in rosacea may only add to the manifestations of this disease, the study suggests.
Meanwhile, the significance of protease activity in rosacea is already backed up by some clinical observations of the condition. For instance, since tetracyclines can indirectly inhibit serine proteases, the role of SCTE may also help explain why those drugs offer therapeutic benefit over other antibiotics for rosacea, despite the fact that skin cultured from rosacea patients often has developed tetracycline-resistant microflora, according to the study.
And preliminary data also suggests that minocycline reduces skin protease activity during treatment; therefore, its efficacy in helping with rosacea symptoms would support the role of protease activity in the condition.
In terms of applying the findings in future therapeutic applications, many more questions would, of course, need to be answered, such as why the peptide levels are abnormal and why the molecules are expressed in the way they are, researchers say. But the two peptide abnormalities offer an important starting point.