Hyperactive Antimicrobial Response Produces Rosacea

Abstract

Rosacea is a painful acne-like skin disorder, characterized by dilated blood vessels causing persistent redness (or erythema), that affects people over the age of 30. Yamasaki et al . provide evidence that the antimicrobial cathelicidin peptides, which are chemotactic, angiogenic, and bactericidal and are important for innate immune responses in the skin, are implicated in the pathogenesis of rosacea. Skin biopsies of patients with rosacea and normal controls were compared, and the rosacea samples had elevated cathelicidin based on immunostaining and analysis of cathelicidin mRNA. In addition, the processed and active form was more abundant in the rosacea samples. Processing involves cleavage of the proprotein near the C terminus, which in human skin is done by the kallikrein family protease stratum corneum tryptic enzyme (SCTE). Rosacea samples had elevated abundance of SCTE compared with normal skin samples, and protease activity was also elevated based on in situ zymography. To ascertain whether the elevated active cathelicidin peptides could contribute to the rosacea symptoms, the most abundant peptides, LL-37 and FA-29, from the rosacea samples were added to cultured human keratinocytes or injected subcutaneously into mice. These rosacea-enriched peptides stimulated interleukin-8 production from the keratinocytes and caused erythema, vascular dilation, neutrophil infiltration, thrombosis, and hemorrhage in the injected skin. Cathelicidin peptides from normal skin did not have these effects on cultured keratinocytes or mouse skin. Injection of SCTE caused similar symptoms. In mice deficient for the gene Camp , which encodes cathelicidin, inflammation was substantially diminished after application of a contact skin irritant or physical abrasion. In mice deficient for the gene encoding the protease inhibitor SPINK5, which inhibits SCTE, the cathelicidin peptide profile was similar to that seen in rosacea. Bevins and Liu discuss the clinical implications of these findings. K. Yamasaki, A. Di Nardo, A. Bardan, M. Murakami, T. Ohtake, A. Coda, R. A. Dorschner, C. Bonnart, P. Descargues, A. Hovnanian, V. B. Morhenn, R. L. Gallo, Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat. Med. 13 , 975-980 (2007). [PubMed] C. L. Bevins, F.-T. Liu, Rosacea: Skin innate immunity gone awry? Nat. Med. 13 , 904-906 (2007). [PubMed]