SAN DIEGO, Aug. 6 -- Acne rosacea appears to be caused by an overly zealous innate immune response and not by bacteria, investigators here said.
Patients with rosacea have significantly higher levels of cathelicidin in facial skin compared with patients who don't have the condition (P=0.015), Richard L. Gallo, M.D., Ph.D., of the University of California at San Diego, and colleagues reported online in Nature Medicine.
Action Points
- Explain to patients that acne rosacea, or "adult" acne, may be caused by an overabundance of naturally occurring antimicrobial proteins in skin, and not, as previously thought, by the bacteria responsible for causing acne vulgaris.
Higher levels combined with an increase in serine protease activity results in the generation of pro-inflammatory forms of the antimicrobial peptide, which in turn cause an inflammatory skin response, they said.
Their finding that rosacea is caused by what Dr. Gallo called a "trifecta of unfortunate factors," points to new avenues of research into inflammatory diseases, the authors reported online in Nature Medicine.
"Influencing the balance of antimicrobial peptides, and their post-secretory processing, provides an opportunity for designing more effective therapy and reveals the potential for the involvement of proteolysis and cathelicidin expression in other inflammatory disorders," they wrote.
Based on laboratory observations that cathelicidin peptides can promote changes in tissue similar to those seen with rosacea, the authors compared biopsy specimens from the naso-malar folds of 11 patients with rosacea and 10 controls with normal facial skin.
They found that all of the samples from the rosacea patients had abundant levels of cathelicidin, as seen with immunostaining.
"Cathelicidin messenger RNA was also evident in rosacea skin by in situ hybridization in contrast to normal epidermis where cathelicidin mRNA is hardly detectable," they wrote. "Thus, we concluded that the skin of individuals with rosacea, similar to that of individuals with other inflammatory diseases expressed more cathelicidin than normal facial skin."
They then looked at how the cathelicidin precursor protein is proteolytically converted into the active antimicrobial peptide, and found that both the levels and processing of the peptides in skin with rosacea were different from those seen in normal skin.
The authors also found that stratum corneum tryptic enzyme was highly expressed in the epidermis of rosacea-affected skin, but not normal skin.
To test the effects of cathelicidin in living skin, the researchers injected peptides from skin with rosacea and normal skin into mice and found that the peptides from rosacea-affected skin, but not those from normal skin, induced an inflammatory response.
They also saw that the addition of stratum corneum tryptic enzyme increased inflammation in the skin of mice, as did targeted deletion in knockout mice of the serine protease inhibitor gene, which cause higher expression of the stratum corneum tryptic enzyme.
Together, the evidence suggests that "too much stratum corneum tryptic enzyme and too much cathelicidin leads to the abnormal peptides that cause the symptoms of this disease," Dr. Gallo said.
"Antibiotics tend to alleviate the symptoms of rosacea in patients because some of them work to inhibit these enzymes," he noted. "Our findings may modify the therapeutic approach to treating rosacea, since bacteria aren't the right target."
| The study was supported by the National Institutes of Health, the National Rosacea Society, a VA Merit Award to Dr. Gallo, and by the Association for Preventive Medicine of Japan. The authors declared no competing financial interests. |
Primary Source
Nature Medicine
Yamasaki K et al. Nature Medicine 2007. doi:10.1038/nm161.