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Published on: March 24, 2017
Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis
Shinji Noda1, Yoshihide Asano1, Satoshi Nishimura2
1Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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.
Insights
Epigenetic suppression of Friend leukaemia integration 1 (Fli1) and Krüppel-like factor 5 (KLF5) drives systemic sclerosis (SSc). Mice lacking these factors develop SSc hallmarks, revealing a unifying pathogenic mechanism.
Area of Science:
- Immunology
- Genetics
- Dermatology
Background:
- Systemic sclerosis (SSc) presents with fibrosis, vasculopathy, and immune dysregulation, lacking a unifying pathogenic hypothesis.
- The multifactorial nature of SSc involves genetic and environmental factors.
- Epigenetic suppression of transcription factors Friend leukaemia integration 1 (Fli1) and Krüppel-like factor 5 (KLF5) occurs in SSc dermal fibroblasts.
Purpose of the Study:
- To investigate the role of Fli1 and KLF5 epigenetic downregulation in SSc pathogenesis.
- To explore the combined effect of Fli1 and KLF5 suppression on fibrotic markers.
- To determine if mimicking the epigenetic phenotype in mice recapitulates SSc features.
Main Methods:
- Investigated Fli1 and KLF5 expression in SSc dermal fibroblasts.
- Performed simultaneous knockdown of Fli1 and KLF5 to assess connective tissue growth factor (CTGF) expression.
- Generated and analyzed mice with double heterozygous deficiency of Klf5 and Fli1.
Main Results:
- Fli1 silencing alone induced collagen production.
- Simultaneous Fli1 and KLF5 knockdown synergistically enhanced CTGF expression.
- Mice with double heterozygous deficiency of Klf5 and Fli1 spontaneously developed SSc features: skin and lung fibrosis, vasculopathy, B-cell activation, and autoantibody production.
Conclusions:
- Epigenetic downregulation of Fli1 and KLF5 is implicated as a central event in SSc.
- This downregulation triggers the pathogenic triad of fibrosis, vasculopathy, and immune dysregulation in SSc.
- The findings provide a unifying hypothesis for SSc pathogenesis.
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