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HIF1α inhibition facilitates Leflunomide-AHR-CRP signaling to attenuate bone erosion in CRP-aberrant rheumatoid arthritis

Author

Listed:
  • Chao Liang

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education)

  • Jie Li

    (Chinese University of Hong Kong)

  • Cheng Lu

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education
    China Academy of Chinese Medical Sciences)

  • Duoli Xie

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education)

  • Jin Liu

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education)

  • Chuanxin Zhong

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education)

  • Xiaohao Wu

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education)

  • Rongchen Dai

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education)

  • Huarui Zhang

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education)

  • Daogang Guan

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education)

  • Baosheng Guo

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education)

  • Bing He

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education)

  • Fangfei Li

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education)

  • Xiaojuan He

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education
    China Academy of Chinese Medical Sciences)

  • Wandong Zhang

    (The First Affiliated Hospital of Anhui University of Chinese Medicine)

  • Bao-Ting Zhang

    (Chinese University of Hong Kong)

  • Ge Zhang

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education)

  • Aiping Lu

    (Hong Kong Baptist University
    Hong Kong Baptist University
    HKBU Institute for Research and Continuing Education
    Guanghua Integrative Medicine Hospital/Shanghai University of TCM)

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive bone erosion. Leflunomide is originally developed to suppress inflammation via its metabolite A77 1726 to attenuate bone erosion. However, distinctive responsiveness to Leflunomide is observed among RA individuals. Here we show that Leflunomide exerts immunosuppression but limited efficacy in RA individuals distinguished by higher serum C-reactive protein (CRPHigher, CRPH), whereas the others with satisfactory responsiveness to Leflunomide show lower CRP (CRPLower, CRPL). CRP inhibition decreases bone erosion in arthritic rats. Besides the immunomodulation via A77 1726, Leflunomide itself induces AHR-ARNT interaction to inhibit hepatic CRP production and attenuate bone erosion in CRPL arthritic rats. Nevertheless, high CRP in CRPH rats upregulates HIF1α, which competes with AHR for ARNT association and interferes Leflunomide-AHR-CRP signaling. Hepatocyte-specific HIF1α deletion or a HIF1α inhibitor Acriflavine re-activates Leflunomide-AHR-CRP signaling to inhibit bone erosion. This study presents a precision medicine-based therapeutic strategy for RA.

Suggested Citation

  • Chao Liang & Jie Li & Cheng Lu & Duoli Xie & Jin Liu & Chuanxin Zhong & Xiaohao Wu & Rongchen Dai & Huarui Zhang & Daogang Guan & Baosheng Guo & Bing He & Fangfei Li & Xiaojuan He & Wandong Zhang & Ba, 2019. "HIF1α inhibition facilitates Leflunomide-AHR-CRP signaling to attenuate bone erosion in CRP-aberrant rheumatoid arthritis," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12163-z
    DOI: 10.1038/s41467-019-12163-z
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