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A critical role of AREG for bleomycin-induced skin fibrosis

Mary Yinghua Zhang, Shuyi Fang, Hongyu Gao, Xiaoli Zhang, Dongsheng Gu, View ORCID ProfileYunlong Liu, Jun Wan, View ORCID ProfileJingwu Xie
doi: https://doi.org/10.1101/2021.01.20.427509
Mary Yinghua Zhang
1The Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indiana
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Shuyi Fang
2Department of BioHealth Informatics, Indiana University School of Informatics and Computing at IUPUI
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Hongyu Gao
3The IU Simon Comprehensive Cancer Center, Indiana University, Indiana
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Xiaoli Zhang
1The Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indiana
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Dongsheng Gu
1The Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indiana
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Yunlong Liu
2Department of BioHealth Informatics, Indiana University School of Informatics and Computing at IUPUI
3The IU Simon Comprehensive Cancer Center, Indiana University, Indiana
4The Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indiana
5Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana
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Jun Wan
2Department of BioHealth Informatics, Indiana University School of Informatics and Computing at IUPUI
3The IU Simon Comprehensive Cancer Center, Indiana University, Indiana
4The Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indiana
5Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana
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Jingwu Xie
1The Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indiana
3The IU Simon Comprehensive Cancer Center, Indiana University, Indiana
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  • For correspondence: jinxie@iu.edu
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ABSTRACT

We report our discovery of an important player in the development of skin fibrosis, a hallmark of scleroderma. Scleroderma is a fibrotic disease, affecting 70,000 to 150,000 Americans. Fibrosis is a pathological wound healing process that produces an excessive extracellular matrix to interfere with normal organ function. Fibrosis contributes to nearly half of human mortality. Scleroderma has heterogeneous phenotypes, unpredictable outcomes, no validated biomarkers, and no effective treatment. Thus, strategies to slow down scleroderma progression represent an urgent medical need. While a pathological wound healing process like fibrosis leaves scars and weakens organ function, oral mucosa wound healing is a scarless process. After re-analyses of gene expression datasets from oral mucosa wound healing and skin fibrosis, we discovered that several pathways constitutively activated in skin fibrosis are transiently induced during oral mucosa wound healing process, particularly the amphiregulin (Areg) gene. Areg expression is upregulated ~10 folds 24hrs after oral mucosa wound but reduced to the basal level 3 days later. During bleomycin-induced skin fibrosis, a commonly used mouse model for skin fibrosis, Areg is up-regulated throughout the fibrogenesis and is associated with elevated cell proliferation in the dermis. To demonstrate the role of Areg for skin fibrosis, we used mice with Areg knockout, and found that Areg deficiency essentially prevents bleomycin-induced skin fibrosis. We further determined that bleomycin-induced cell proliferation in the dermis was not observed in the Areg null mice. Furthermore, we found that inhibiting MEK, a downstream signaling effector of Areg, by selumetinib also effectively blocked bleomycin-based skin fibrosis model. Based on these results, we concluded that the Areg-EGFR-MEK signaling axis is critical for skin fibrosis development. Blocking this signaling axis may be effective in treating scleroderma.

Competing Interest Statement

The authors have declared no competing interest.

  • LIST OF ABBREVIATIONS

    AREG
    amphiregulin
    ECM
    extracellular matrix
    MEK
    MAPK/ERK kinase
    ERK
    extracellular receptor-stimulated kinase
    MAPK
    mitogen-activated protein kinase.
    EGFR
    Epidermal Growth Factor Receptor
    H&E
    Hematoxylin and Eosin
    ILC2
    group 2 innate lymphoid cells
    IL33
    Interleukin 33
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    Posted January 21, 2021.
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    A critical role of AREG for bleomycin-induced skin fibrosis
    Mary Yinghua Zhang, Shuyi Fang, Hongyu Gao, Xiaoli Zhang, Dongsheng Gu, Yunlong Liu, Jun Wan, Jingwu Xie
    bioRxiv 2021.01.20.427509; doi: https://doi.org/10.1101/2021.01.20.427509
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    A critical role of AREG for bleomycin-induced skin fibrosis
    Mary Yinghua Zhang, Shuyi Fang, Hongyu Gao, Xiaoli Zhang, Dongsheng Gu, Yunlong Liu, Jun Wan, Jingwu Xie
    bioRxiv 2021.01.20.427509; doi: https://doi.org/10.1101/2021.01.20.427509

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