Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis

Shinji Noda, Yoshihide Asano (), Satoshi Nishimura, Takashi Taniguchi, Katsuhito Fujiu, Ichiro Manabe, Kouki Nakamura, Takashi Yamashita, Ryosuke Saigusa, Kaname Akamata, Takehiro Takahashi, Yohei Ichimura, Tetsuo Toyama, Daisuke Tsuruta, Maria Trojanowska, Ryozo Nagai and Shinichi Sato ()
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Shinji Noda: the University of Tokyo Graduate School of Medicine
Yoshihide Asano: the University of Tokyo Graduate School of Medicine
Satoshi Nishimura: the University of Tokyo Graduate School of Medicine
Takashi Taniguchi: the University of Tokyo Graduate School of Medicine
Katsuhito Fujiu: the University of Tokyo Graduate School of Medicine
Ichiro Manabe: the University of Tokyo Graduate School of Medicine
Kouki Nakamura: the University of Tokyo Graduate School of Medicine
Takashi Yamashita: the University of Tokyo Graduate School of Medicine
Ryosuke Saigusa: the University of Tokyo Graduate School of Medicine
Kaname Akamata: the University of Tokyo Graduate School of Medicine
Takehiro Takahashi: the University of Tokyo Graduate School of Medicine
Yohei Ichimura: the University of Tokyo Graduate School of Medicine
Tetsuo Toyama: the University of Tokyo Graduate School of Medicine
Daisuke Tsuruta: Osaka City University Graduate School of Medicine
Maria Trojanowska: Arthritis Center, Rheumatology, Boston University School of Medicine
Ryozo Nagai: the University of Tokyo Graduate School of Medicine
Shinichi Sato: the University of Tokyo Graduate School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-17

Abstract: Abstract Systemic sclerosis (SSc) is manifested by fibrosis, vasculopathy and immune dysregulation. So far, a unifying hypothesis underpinning these pathological events remains unknown. Given that SSc is a multifactorial disease caused by both genetic and environmental factors, we focus on the two transcription factors, which modulate the fibrotic reaction and are epigenetically suppressed in SSc dermal fibroblasts, Friend leukaemia integration 1 (Fli1) and Krüppel-like factor 5 (KLF5). In addition to the Fli1 silencing-dependent collagen induction, the simultaneous knockdown of Fli1 and KLF5 synergistically enhances expression of connective tissue growth factor. Notably, mice with double heterozygous deficiency of Klf5 and Fli1 mimicking the epigenetic phenotype of SSc skin spontaneously recapitulate all the three features of SSc, including fibrosis and vasculopathy of the skin and lung, B-cell activation and autoantibody production. These studies implicate the epigenetic downregulation of Fli1 and KLF5 as a central event triggering the pathogenic triad of SSc.

Date: 2014
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DOI: 10.1038/ncomms6797

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