Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea

Abstract

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 telangiectasia1,2,3. 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 peptides4. 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.

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Figure 1: Cathelicidin is abundant in rosacea.
Figure 2: Altered expression of cathelicidin peptides in rosacea skin.
Figure 3: Increased SCTE expression and protease activity in rosacea epidermis.
Figure 4: Cathelicidin peptides augment cytokine induction in human keratinocytes and skin inflammation.

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Acknowledgements

We thank B. Cottrell for instructions in SELDI-TOF-MS analysis. This work was supported by the National Institutes of Health (R01-AI052453, R01-AR45676), The National Rosacea Society and a VA Merit Award (R.L.G.); and the Association for Preventive Medicine of Japan (K.Y.).

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K.Y. conducted SELDI-TOF-MS experiments, protease assays including in situ zymography and in vivo studies, and wrote the manuscript. A.D.N. conducted the in vivo skin irritation model. A.B., M.M. and T.O. performed immunohistochemistry, dot blot and in situ hybridization. A.C. performed immunofluorescence. R.A.D. prepared and purified peptides. C.B., P.D. and A.H. contributed to the experiments with Spink5-deficient mice. A.B., V.B.M. and R.L.G. organized human sample collection. R.L.G. conceived, designed and supervised all aspects of this work.

Corresponding author

Correspondence to Richard L Gallo.

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The authors declare no competing financial interests.

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Supplementary Figs. 1–4, Supplementary Methods (PDF 886 kb)

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Yamasaki, K., Di Nardo, A., Bardan, A. et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med 13, 975–980 (2007). https://doi.org/10.1038/nm1616

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