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Fli1 deficiency contributes to the suppression of endothelial CXCL5 expression in systemic sclerosis

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Abstract

CXCL5 is a member of CXC chemokines with neutrophilic chemoattractant and pro-angiogenic properties, which has been implicated in the pathological angiogenesis of rheumatoid arthritis and inflammatory bowel diseases. Since aberrant angiogenesis is also involved in the developmental process of systemic sclerosis (SSc), we herein measured serum CXCL5 levels in 63 SSc and 18 healthy subjects and investigated their clinical significance and the mechanism explaining altered expression of CXCL5 in SSc. Serum CXCL5 levels were significantly lower in SSc patients than in healthy subjects. In diffuse cutaneous SSc (dcSSc), serum CXCL5 levels were uniformly decreased in early stage (<1 year) and positively correlated with disease duration in patients with disease duration of <6 years. In non-early stage dcSSc (≥1 year), decreased serum CXCL5 levels were linked to the development of digital ulcers. Consistently, the expression levels of CXCL5 proteins were decreased in dermal blood vessels of early stage dcSSc. Importantly, Fli1 bound to the CXCL5 promoter and its gene silencing significantly suppressed the CXCL5 mRNA expression in human dermal microvascular endothelial cells. Furthermore, endothelial cell-specific Fli1 knockout mice, an animal model of SSc vasculopathy, exhibited decreased CXCL5 expression in dermal blood vessels. Collectively, these results indicate that CXCL5 is a member of angiogenesis-related genes, whose expression is suppressed at least partially due to Fli1 deficiency in SSc endothelial cells. Since Fli1 deficiency is deeply related to aberrant angiogenesis in SSc, it is plausible that serum CXCL5 levels inversely reflect the severity of SSc vasculopathy.

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Acknowledgments

We thank Tamami Kaga and Yoshiko Ito for the technical help in cell culture and immunohistochemistry. This work was supported by a grant for Research on Intractable Diseases from the Ministry of Health, Labour, and Welfare of Japan.

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The authors declare that they have no conflict of interest.

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Correspondence to Yoshihide Asano or Takafumi Kadono.

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Ichimura, Y., Asano, Y., Akamata, K. et al. Fli1 deficiency contributes to the suppression of endothelial CXCL5 expression in systemic sclerosis. Arch Dermatol Res 306, 331–338 (2014). https://doi.org/10.1007/s00403-013-1431-9

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  • DOI: https://doi.org/10.1007/s00403-013-1431-9

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