Koebnerisin (S100A15): A novel player in the pathogenesis of rosacea

Rosacea is one of the most common chronic inflammatory skin diseases that mainly affects the white adult population. The pathophysiology of rosacea is still not completely elucidated. Growing evidence indicates that the aberrant innate immune response might play an essential role in this disease.1Gallo R.L. Granstein R.D. Kang S. et al.Standard classification and pathophysiology of rosacea: the 2017 update by the National Rosacea Society Expert Committee.J Am Acad Dermatol. 2018; 78: 148-155Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar S100 proteins are a family of small (9-13 kDa), calcium-binding molecules involved in the regulation of cell signaling, metabolism, and proliferation. A member of the S100 protein family, koebnerisin (S100A15), is an innate, antimicrobial peptide with diverse proinflammatory functions encoded by a gene located within the epidermal differentiation complex on chromosome 1q21. The S100A15 gene is transcribed into 2 alternate mRNA splice variants, the short (S100A15-S) and long (S100A15-L) isoforms, that share the same coding region but are differentially regulated.2Wolf R. Ruzicka T. Yuspa S.H. Novel S100A7 (Psoriasin)/S100A15 (koebnerisin) subfamily: highly homologous but distinct in regulation and function.Amino Acids. 2011; 41: 789-796Crossref PubMed Scopus (59) Google Scholar Koebnerisin has been shown to act as an alarmin or has a danger-associated molecular pattern (DAMP). In response to some endogenous or exogenous stimuli, koebnerisin enhances immune-mediated inflammatory processes in the skin.2Wolf R. Ruzicka T. Yuspa S.H. Novel S100A7 (Psoriasin)/S100A15 (koebnerisin) subfamily: highly homologous but distinct in regulation and function.Amino Acids. 2011; 41: 789-796Crossref PubMed Scopus (59) Google Scholar, 3Wolf R. Howard O.M. Dong H.F. et al.Chemotactic activity of S100A7 (Psoriasin) is mediated by the receptor for advanced glycation end products and potentiates inflammation with highly homologous but functionally distinct S100A15.J Immunol. 2008; 181: 1499-1506Crossref PubMed Scopus (136) Google Scholar, 4Hegyi Z. Zwicker S. Bureik D. et al.Vitamin D analog calcipotriol suppresses the Th17 cytokine-induced proinflammatory S100 “alarmins” Psoriasin (S100A7) and koebnerisin (S100A15) in psoriasis.J Invest Dermatol. 2012; 132: 1416-1424Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar Koebnerisin was first found to be up-regulated in psoriatic skin lesions; however, it also appears to play an important role in other chronic inflammatory skin diseases, such as acne vulgaris.2Wolf R. Ruzicka T. Yuspa S.H. Novel S100A7 (Psoriasin)/S100A15 (koebnerisin) subfamily: highly homologous but distinct in regulation and function.Amino Acids. 2011; 41: 789-796Crossref PubMed Scopus (59) Google Scholar, 5Borovaya A. Dombrowski Y. Zwicker S. et al.Isotretinoin therapy changes the expression of antimicrobial peptides in acne vulgaris.Arch Dermatol Res. 2014; 306: 689-700Google Scholar In inflamed skin, koebnerisin is expressed by various cells, such as keratinocytes, fibroblast, endothelial cells, and dendritic cells.2Wolf R. Ruzicka T. Yuspa S.H. Novel S100A7 (Psoriasin)/S100A15 (koebnerisin) subfamily: highly homologous but distinct in regulation and function.Amino Acids. 2011; 41: 789-796Crossref PubMed Scopus (59) Google Scholar The role of koebnerisin in rosacea has not been investigated. The objective of the present study was to investigate the expression and function of koebnerisin in rosacea. The study group consisted of patients with moderate and severe rosacea (n = 6). Skin biopsies were taken from inflammatory, erythematopapular lesions located on the face. All patients were white, had skin of phototype I-III, and were 47-66 (mean ± standard deviation 56.83 ± 7.03) years of age. The control group was matched by race, sex, and age and consisted of healthy volunteers who underwent facial plastic surgery procedures (n = 6). The expression of koebnerisin in skin lesions of patients with rosacea and controls was assessed by quantitative reverse transcription PCR and immunofluorescent analysis. The regulation and function of koebnerisin in rosacea-relevant human skin cell cultures, keratinocytes, and fibroblasts were assessed by quantitative reverse transcription PCR. In the present study, we found that koebnerisin was upregulated in rosacea lesional skin compared with healthy skin (Fig 1). Koebnerisin was overexpressed in the epidermis by suprabasal and basal keratinocytes as well as in the dermis. The upregulation of koebnerisin in the epidermis suggests its potential role in the regulation of keratinocytes proliferation and function. Moreover, by being overexpressed in rosacea skin lesions, koebnerisin might exert a proinflammatory effect. A previously conducted study showed that koebnerisin acts as a chemoattractant for monocytes and neutrophils, which play a significant role in the pathogenesis of rosacea.3Wolf R. Howard O.M. Dong H.F. et al.Chemotactic activity of S100A7 (Psoriasin) is mediated by the receptor for advanced glycation end products and potentiates inflammation with highly homologous but functionally distinct S100A15.J Immunol. 2008; 181: 1499-1506Crossref PubMed Scopus (136) Google Scholar Furthermore, it has been demonstrated that koebnerisin has the ability to prime keratinocytes and leukocytes for enhanced production of proinflammatory cytokines, eg, tumor necrosis factor α (TNF-α), interleukin (IL) 6, IL-8, and IL-1β.4Hegyi Z. Zwicker S. Bureik D. et al.Vitamin D analog calcipotriol suppresses the Th17 cytokine-induced proinflammatory S100 “alarmins” Psoriasin (S100A7) and koebnerisin (S100A15) in psoriasis.J Invest Dermatol. 2012; 132: 1416-1424Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 6Batycka-Baran A. Hattinger E. Zwicker S. et al.Leukocyte-derived koebnerisin (S100A15) and Psoriasin (S100A7) are systemic mediators of inflammation in psoriasis.J Dermatol Sci. 2015; 79: 214-221Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Recent studies have indicated a significant role for TNF-α and IL-1β in rosacea.1Gallo R.L. Granstein R.D. Kang S. et al.Standard classification and pathophysiology of rosacea: the 2017 update by the National Rosacea Society Expert Committee.J Am Acad Dermatol. 2018; 78: 148-155Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar We also demonstrated that TNF-α enhanced the expression of koebnerisin in keratinocytes and fibroblasts (Fig 2, A and B), which might create a vicious circular cycle of inflammation. In the present study, we also showed that koebnerisin might play an additional proangiogenic role stimulating keratinocytes and fibroblasts to enhance the production of the potent proangiogenic mediator vascular endothelial growth factor, and we further demonstrated that koebnerisin primed fibroblasts for increased expression of matrix metalloproteinase 9 (Fig 2, C-F). Matrix metalloproteinase 9 has a destructive effect on dermal components and, thus, stimulates the innate immune response and inflammatory processes.1Gallo R.L. Granstein R.D. Kang S. et al.Standard classification and pathophysiology of rosacea: the 2017 update by the National Rosacea Society Expert Committee.J Am Acad Dermatol. 2018; 78: 148-155Abstract Full Text Full Text PDF PubMed Scopus (224) Google ScholarFig 2Quantitative reverse transcription PCR of mRNA in healthy human skin and lesional skin from patients with moderate and severe rosacea. A and B, Koebnerisin (S100A15) enhances the expression of VEGF and does not influence the expression of MMP-9 in human keratinocytes. C and D, Koebnerisin enhances the expression of VEGF and MMP-9 in human fibroblasts. E, TNF-α and IL-17A enhances the expression of koebnerisin in human keratinocytes F, TNF-α enhances the expression of koebnerisin in human fibroblasts. Data represent mean ± standard error of mean. *P = .05. IL-17A, Interleukin 17A; MMP-9, matrix metalloproteinase-9; TNF-α, tumor necrosis factor α; VEGF, vascular endothelial growth factor.View Large Image Figure ViewerDownload Hi-res image Download (PPT) In conclusion, koebnerisin (S100A15) might emerge as a novel player in the pathogenesis of rosacea. Balancing the activities of certain antimicrobial proteins might be a goal for future therapeutic interventions in rosacea.