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A potential contribution of antimicrobial peptide LL‐37 to tissue fibrosis and vasculopathy in systemic sclerosis
Author(s) -
Takahashi T.,
Asano Y.,
Nakamura K.,
Yamashita T.,
Saigusa R.,
Ichimura Y.,
Toyama T.,
Taniguchi T.,
Yoshizaki A.,
Tamaki Z.,
Tada Y.,
Sugaya M.,
Kadono T.,
Sato S.
Publication year - 2016
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.14699
Subject(s) - fli1 , angiogenesis , downregulation and upregulation , immunostaining , fibrosis , biology , reverse transcription polymerase chain reaction , pathology , immunology , microbiology and biotechnology , medicine , gene expression , cancer research , immunohistochemistry , transcription factor , gene , biochemistry
Summary Background LL ‐37 is an antimicrobial peptide with pleiotropic effects on the immune system, angiogenesis and tissue remodelling. These are cardinal pathological events in systemic sclerosis ( SS c). Objectives To elucidate the potential role of LL ‐37 in SS c. Methods The expression of target molecules was evaluated by immunostaining and quantitative reverse‐transcription real‐time polymerase chain reaction in human and murine skin. The mechanisms regulating LL ‐37 expression in endothelial cells were examined by gene silencing and chromatin immunoprecipitation. Serum LL ‐37 levels were determined by enzyme‐linked immunosorbent assay. Results In SS c lesional skin, LL ‐37 expression was increased in dermal fibroblasts, perivascular inflammatory cells, keratinocytes and, particularly, dermal small vessels. Expression positively correlated with interferon‐α expression, possibly reflecting LL ‐37‐dependent induction of interferon‐α. In SS c animal models, bleomycin‐treated skin exhibited the expression pattern of CRAMP , a murine homologue of LL ‐37, similar to that of LL ‐37 in SS c lesional skin. Furthermore, Fli1 +/− mice showed upregulated expression of CRAMP in dermal small vessels. Fli1 binding to the CAMP ( LL ‐37 gene) promoter and Fli1 deficiency‐dependent induction of LL ‐37 were also confirmed in human dermal microvascular endothelial cells. In the analysis of sera, patients with SS c had serum LL ‐37 levels significantly higher than in healthy controls. Furthermore, serum LL ‐37 levels positively correlated with skin score and the activity of alveolitis and were significantly elevated in patients with digital ulcers compared with those without. Conclusions LL ‐37 upregulation, induced by Fli1 deficiency at least in endothelial cells, potentially contributes to the development of skin sclerosis, interstitial lung disease and digital ulcers in SS c.