Highlights
- •DAB2 expression was enhanced in the skin of SSc patients and DAB2 knockdown ameliorated skin fibrosis induced by BLM.
- •DAB2 knockdown suppressed the number of inflammatory cells and inflammatory gene expression in BLM-induced mouse skin.
- •DAB2 knockdown suppressed the activation of skin fibroblasts.
- •Transcriptome analysis of DAB2 siRNA transfected SSc skin fibroblasts.
Abstract
Background
Systemic sclerosis (SSc) is a connective tissue disease characterized by inflammation
and fibrosis. Our previous research found Disabled-2 (DAB2) expression was significantly
downregulated by salvianolic acid B, a small molecular medicine which attenuated experimental
skin fibrosis of SSc. These suggest that DAB2 plays an important role in SSc skin
fibrosis, but the role of DAB2 in SSc remains unclear.
Objectives
To investigate the role of DAB2 in SSc.
Methods
DAB2 expression level was detected in the skin and peripheral blood mononuclear cells
of SSc patients. Bleomycin (BLM)-induced SSc mice and primary SSc skin fibroblasts
were used to investigate the effect of DAB2 downregulation on fibrosis. RNA-seq transcriptome
analysis was performed to underlie the mechanism of DAB2 in fibroblasts.
Results
DAB2 expression was enhanced in SSc lesion skin and was positively correlated with
fibrotic genes, such as α-SMA and PAI-1. The in vivo study revealed that DAB2 downregulation alleviated skin fibrosis, alleviating skin
thickness and reducing collagen deposition, and DAB2 knockdown ameliorated the inflammatory
cell infiltration. The in vitro study showed that DAB2 knockdown reduced extracellular matrix genes and proteins
expression. Moreover, Transcriptome analysis revealed TGF-β and focal adhesion signaling
pathways were the main downregulated pathways involved in DAB2 siRNA treated fibroblasts.
Conclusions
Taken together, our results revealed that DAB2 was increased in SSc skin, and DAB2
downregulation inhibited BLM-induced mouse skin fibrosis and SSc skin fibroblasts
activation. DAB2 played an important role in the pathogenesis of SSc and DAB2 modulation
may represent a potential therapeutic method for SSc.
Keywords
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Article info
Publication history
Published online: June 02, 2020
Accepted:
May 24,
2020
Received in revised form:
May 20,
2020
Received:
November 17,
2019
Identification
Copyright
© 2020 Published by Elsevier B.V. on behalf of Japanese Society for Investigative Dermatology.
