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Cathelicidins, antimicrobial peptides produced in the epidermis and other organs, protect the skin against infection by gram-positive and gram-negative bacteria. Important components of the innate immune system, these agents also have proinflammatory properties. They are secreted as inactive precursors that undergo enzymatic cleavage to take on their functional form. Here, researchers have investigated the role of cathelicidins in the pathogenesis of rosacea.
The investigators found abundant levels of cathelicidins in biopsy samples of facial skin taken from rosacea patients but minimal levels in skin samples from healthy control subjects. In addition to being more abundant, the cathelicidins in rosacea patients were different in type. Compared with controls, rosacea patients had many more active cathelicidin peptides, which stimulated the production of proinflammatory cytokines in keratinocytes; these patients also had other evidence of abnormal cathelicidin expression and processing. Moreover, increased levels of stratum corneum tryptic enzyme (SCTE, also known as kallikrein 5), the enzyme that cleaves the inactive cathelicidin precursor into its functionally active form, were found in patients with rosacea-affected skin, expressed throughout the epidermis. By contrast, the skin of healthy controls had smaller amounts of SCTE, and it was found only in the stratum corneum and the granular layer. The investigators were able to reproduce the inflammatory characteristics of rosacea in mice by injecting active cathelicidin peptides, adding SCTE, or increasing protease activity. These responses, however, were absent in mice with a deleted cathelicidin gene.
Yamasaki K et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med 2007 Aug; 13:975-80.
Comment
These findings present persuasive evidence that overexpression of the enzyme that cleaves cathelicidin produces the clinical manifestations of rosacea. As we learn more about the innate immune system and its various components, we are identifying the basis of many previously perplexing diseases. For example, toll-like receptors have been shown to be activated by Propionibacterium acnes, and granulysin — another antimicrobial and proinflammatory peptide of the innate immune system — has been implicated in the pathogenesis of acne vulgaris. This study illustrates how advances in basic research can promote insight into the nature of human disease.