Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea.
Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia. The etiology of this disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis. In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.
Division of Dermatology, University of California, San Diego, and VA San Diego Health Care System, 3350 La Jolla Village Drive, San Diego, California 92161, USA.
Kenshi
K
Yamasaki
Anna
A
Di Nardo
Antonella
A
Bardan
Masamoto
M
Murakami
Takaaki
T
Ohtake
Alvin
A
Coda
Robert A
RA
Dorschner
Chrystelle
C
Bonnart
Pascal
P
Descargues
Alain
A
Hovnanian
Vera B
VB
Morhenn
Richard L
RL
Gallo
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001706:Biopsy; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012393:Rosacea / Q000378:metabolism* / Q000473:pathology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015843:Serpins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015843:Serpins; C495972:Spink5 protein, mouse; D012697:Serine Endopeptidases; D054804:Cathelicidins