Endothelial CCR6 expression due to FLI1 deficiency contributes to vasculopathy associated with systemic sclerosis

Abstract Background We have recently demonstrated that serum CCL20 levels positively correlate with mean pulmonary arterial pressure in patients with systemic sclerosis (SSc). Considering a proangiogenic effect of CCL20 on endothelial cells via CCR6, the CCL20/CCR6 axis may contribute to the develop...

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Autores principales:	Tetsuya Ikawa, Takuya Miyagawa, Yuki Fukui, Satoshi Toyama, Jun Omatsu, Kentaro Awaji, Yuta Norimatsu, Yusuke Watanabe, Ayumi Yoshizaki, Shinichi Sato, Yoshihide Asano
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Systemic sclerosis CCL20 CCR6 FLI1 Endothelial cells Diseases of the musculoskeletal system RC925-935
Acceso en línea:	https://doaj.org/article/0e9cdce30672437283f148d5d64ac7bc
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spelling	oai:doaj.org-article:0e9cdce30672437283f148d5d64ac7bc2021-11-14T12:07:12ZEndothelial CCR6 expression due to FLI1 deficiency contributes to vasculopathy associated with systemic sclerosis10.1186/s13075-021-02667-91478-6362https://doaj.org/article/0e9cdce30672437283f148d5d64ac7bc2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13075-021-02667-9https://doaj.org/toc/1478-6362Abstract Background We have recently demonstrated that serum CCL20 levels positively correlate with mean pulmonary arterial pressure in patients with systemic sclerosis (SSc). Considering a proangiogenic effect of CCL20 on endothelial cells via CCR6, the CCL20/CCR6 axis may contribute to the development of SSc vasculopathy. Therefore, we explored this hypothesis using clinical samples, cultured cells, and murine SSc models. Methods The expression levels of CCL20 and CCR6 in the skin, mRNA levels of target genes, and the binding of transcription factor FLI1 to the target gene promoter were evaluated by immunostaining, quantitative reverse transcription PCR, and chromatin immunoprecipitation, respectively. Vascular permeability was evaluated by Evans blue dye injection in bleomycin-treated mice. Angiogenic activity of endothelial cells was assessed by in vitro angiogenesis assay. Results CCL20 expression was significantly elevated in dermal fibroblasts of patients with early diffuse cutaneous SSc, while CCR6 was significantly up-regulated in dermal small vessels of SSc patients irrespective of disease subtypes and disease duration. In human dermal microvascular endothelial cells, FLI1 siRNA induced the expression of CCR6, but not CCL20, and FLI1 bound to the CCR6 promoter. Importantly, vascular permeability, a representative SSc-like vascular feature of bleomycin-treated mice, was attenuated by Ccr6 siRNA treatment, and CCR6 siRNA suppressed the angiogenic activity of human dermal microvascular endothelial cells assayed by in vitro tube formation. Conclusions The increased expression of endothelial CCR6 due to FLI1 deficiency may contribute to the development of SSc vasculopathy.Tetsuya IkawaTakuya MiyagawaYuki FukuiSatoshi ToyamaJun OmatsuKentaro AwajiYuta NorimatsuYusuke WatanabeAyumi YoshizakiShinichi SatoYoshihide AsanoBMCarticleSystemic sclerosisCCL20CCR6FLI1Endothelial cellsDiseases of the musculoskeletal systemRC925-935ENArthritis Research & Therapy, Vol 23, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Systemic sclerosis CCL20 CCR6 FLI1 Endothelial cells Diseases of the musculoskeletal system RC925-935
spellingShingle	Systemic sclerosis CCL20 CCR6 FLI1 Endothelial cells Diseases of the musculoskeletal system RC925-935 Tetsuya Ikawa Takuya Miyagawa Yuki Fukui Satoshi Toyama Jun Omatsu Kentaro Awaji Yuta Norimatsu Yusuke Watanabe Ayumi Yoshizaki Shinichi Sato Yoshihide Asano Endothelial CCR6 expression due to FLI1 deficiency contributes to vasculopathy associated with systemic sclerosis
description	Abstract Background We have recently demonstrated that serum CCL20 levels positively correlate with mean pulmonary arterial pressure in patients with systemic sclerosis (SSc). Considering a proangiogenic effect of CCL20 on endothelial cells via CCR6, the CCL20/CCR6 axis may contribute to the development of SSc vasculopathy. Therefore, we explored this hypothesis using clinical samples, cultured cells, and murine SSc models. Methods The expression levels of CCL20 and CCR6 in the skin, mRNA levels of target genes, and the binding of transcription factor FLI1 to the target gene promoter were evaluated by immunostaining, quantitative reverse transcription PCR, and chromatin immunoprecipitation, respectively. Vascular permeability was evaluated by Evans blue dye injection in bleomycin-treated mice. Angiogenic activity of endothelial cells was assessed by in vitro angiogenesis assay. Results CCL20 expression was significantly elevated in dermal fibroblasts of patients with early diffuse cutaneous SSc, while CCR6 was significantly up-regulated in dermal small vessels of SSc patients irrespective of disease subtypes and disease duration. In human dermal microvascular endothelial cells, FLI1 siRNA induced the expression of CCR6, but not CCL20, and FLI1 bound to the CCR6 promoter. Importantly, vascular permeability, a representative SSc-like vascular feature of bleomycin-treated mice, was attenuated by Ccr6 siRNA treatment, and CCR6 siRNA suppressed the angiogenic activity of human dermal microvascular endothelial cells assayed by in vitro tube formation. Conclusions The increased expression of endothelial CCR6 due to FLI1 deficiency may contribute to the development of SSc vasculopathy.
format	article
author	Tetsuya Ikawa Takuya Miyagawa Yuki Fukui Satoshi Toyama Jun Omatsu Kentaro Awaji Yuta Norimatsu Yusuke Watanabe Ayumi Yoshizaki Shinichi Sato Yoshihide Asano
author_facet	Tetsuya Ikawa Takuya Miyagawa Yuki Fukui Satoshi Toyama Jun Omatsu Kentaro Awaji Yuta Norimatsu Yusuke Watanabe Ayumi Yoshizaki Shinichi Sato Yoshihide Asano
author_sort	Tetsuya Ikawa
title	Endothelial CCR6 expression due to FLI1 deficiency contributes to vasculopathy associated with systemic sclerosis
title_short	Endothelial CCR6 expression due to FLI1 deficiency contributes to vasculopathy associated with systemic sclerosis
title_full	Endothelial CCR6 expression due to FLI1 deficiency contributes to vasculopathy associated with systemic sclerosis
title_fullStr	Endothelial CCR6 expression due to FLI1 deficiency contributes to vasculopathy associated with systemic sclerosis
title_full_unstemmed	Endothelial CCR6 expression due to FLI1 deficiency contributes to vasculopathy associated with systemic sclerosis
title_sort	endothelial ccr6 expression due to fli1 deficiency contributes to vasculopathy associated with systemic sclerosis
publisher	BMC
publishDate	2021
url	https://doaj.org/article/0e9cdce30672437283f148d5d64ac7bc
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Endothelial CCR6 expression due to FLI1 deficiency contributes to vasculopathy associated with systemic sclerosis

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