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A novel molecular mechanism of vascular fibrosis in Takayasu arteritis: macrophage-derived GPNMB promoting adventitial fibroblast extracellular matrix production in the aorta

  • Author Footnotes
    # Xiaojuan Dai, Ying Sun and Lingying Ma contributed equally to this work and should be considered co-first authors.
    Xiaojuan Dai
    Footnotes
    # Xiaojuan Dai, Ying Sun and Lingying Ma contributed equally to this work and should be considered co-first authors.
    Affiliations
    Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
    Search for articles by this author
  • Author Footnotes
    # Xiaojuan Dai, Ying Sun and Lingying Ma contributed equally to this work and should be considered co-first authors.
    Ying Sun
    Footnotes
    # Xiaojuan Dai, Ying Sun and Lingying Ma contributed equally to this work and should be considered co-first authors.
    Affiliations
    Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
    Search for articles by this author
  • Author Footnotes
    # Xiaojuan Dai, Ying Sun and Lingying Ma contributed equally to this work and should be considered co-first authors.
    Lingying Ma
    Footnotes
    # Xiaojuan Dai, Ying Sun and Lingying Ma contributed equally to this work and should be considered co-first authors.
    Affiliations
    Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
    Search for articles by this author
  • Jun Hou
    Affiliations
    Department of Pathology, Zhongshan Hospital Fudan University, Shanghai, China
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  • Li Wang
    Affiliations
    Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
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  • Yu Gong
    Affiliations
    Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
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  • Xiaoning Sun
    Affiliations
    Department of Cardiac Surgery, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
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  • Sifan Wu
    Affiliations
    Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
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  • Jinghua Wang
    Affiliations
    Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
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  • Zongfei Ji
    Affiliations
    Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
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  • Huiyong Chen
    Affiliations
    Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
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  • Lili Ma
    Affiliations
    Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
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  • Lindi Jiang
    Correspondence
    Reprint requests: Department of Rheumatology, Zhongshan Hospital, Fudan University, No.180, Fenglin Road, Xuhui District, Shanghai, 200032, China.
    Affiliations
    Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China

    Center of Clinical Epidemiology and Evidence-based Medicine, Fudan University, Shanghai, China
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  • Xiufang Kong
    Correspondence
    Reprint requests: Department of Rheumatology, Zhongshan Hospital, Fudan University, No.180, Fenglin Road, Xuhui District, Shanghai, 200032, China.
    Affiliations
    Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China

    Center of Clinical Epidemiology and Evidence-based Medicine, Fudan University, Shanghai, China
    Search for articles by this author
  • Author Footnotes
    # Xiaojuan Dai, Ying Sun and Lingying Ma contributed equally to this work and should be considered co-first authors.
Published:December 21, 2022DOI:https://doi.org/10.1016/j.trsl.2022.12.004

      Abstract

      Takayasu arteritis (TAK) is a chronic large vessel disease characterized by aortic fibrotic thickening, which was mainly mediated by activation of aorta adventitial fibroblasts (AAFs). Our previous genetic study demonstrated that TAK-associated locus IL6 rs2069837 regulated glycoprotein non-metastatic melanoma protein B (GPNMB) expression. Thus, this study aimed to investigate the pathogenic role of GPNMB in TAK. Through pathological staining, we find that GPNMB was mainly expressed in vascular adventitia and positively correlated with adventitial extracellular matrix (ECM) expression in TAK vascular lesion. Specifically, GPNMB was increased in adventitial CD68+ macrophages, which were closely located with CD90+ adventitial fibroblasts. In in-vitro cell culture, THP-1-derived macrophages with GPNMB overexpression promoted ECM expression in AAFs. This effect was also confirmed in aortic tissue or AAFs culture with GPNMB overexpression or active GPNMB protein stimulation. Mechanistically, Co-IP assay and siRNA or inhibitor intervention demonstrated that integrin αVβ1 receptor mediated GPNMB effect on AAFs, which also activated downstream Akt and Erk pathway in AAFs. Furthermore, we showed that leflunomide treatment inhibited GPNMB-mediated fibrosis in AAFs, as well as GPNMB expression in macrophages, which were also partially validated in leflunomide-treated patients. Taken together, these data indicated that macrophage-derived GPNMB promotes AAFs ECM expression via the integrin αVβ1 receptor and Akt/Erk signaling pathway and leflunomide might play an anti-fibrotic role in TAK by interfering with the macrophage-derived GPNMB/AAFs axis. This study provides evidence that targeting GPNMB is a potential therapeutic strategy for treating vascular fibrosis in TAK.

      Keywords

      Abbreviations:

      AAFs (aorta adventitial fibroblasts), ACR (the American College of Rheumatology), COL1 (Collagen I), Co-IP (Co-immunoprecipitation), ECM (extracellular matrix), FN (fibronectin), GPNMB (glycoprotein non-metastatic melanoma protein B), MMP9 (matrix metalloprotein 9), MMP2 (matrix metalloprotein 2), MRA (magnetic resonance angiography), NIH (the National Institutes of Health), PBMCs (peripheral blood mononuclear cells), sGPNMB (soluble GPNMB), TAK (takayasu arteritis), TGF-β (Transforming growth factor-β)
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