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TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s disease

Author

Listed:
  • Menghao Zhang

    (The Ministry of Education Key Laboratory)

  • Na Kang

    (Tsinghua University)

  • Xin Yu

    (The Ministry of Education Key Laboratory)

  • Xiaoyang Zhang

    (Tsinghua University)

  • Qinghui Duan

    (Tsinghua University)

  • Xianqiang Ma

    (Tsinghua University)

  • Qiancheng Zhao

    (Tsinghua University)

  • Zhimian Wang

    (The Ministry of Education Key Laboratory)

  • Xiao’ou Wang

    (The Ministry of Education Key Laboratory)

  • Yeling Liu

    (The Ministry of Education Key Laboratory)

  • Yuxiao Zhang

    (Tsinghua University)

  • Can Zhu

    (Tsinghua University)

  • Ruiyu Gao

    (Tsinghua University)

  • Xin Min

    (Tsinghua University)

  • Cuifeng Li

    (Tsinghua University)

  • Jin Jin

    (the Third Affiliated Hospital of Sun Yat-sen University)

  • Qian Cao

    (Zhejiang University)

  • Rongbei Liu

    (Zhejiang University)

  • Xiaoyin Bai

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Hong Yang

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Lidan Zhao

    (The Ministry of Education Key Laboratory)

  • Jinjing Liu

    (The Ministry of Education Key Laboratory)

  • Hua Chen

    (The Ministry of Education Key Laboratory)

  • Yonghui Zhang

    (Tsinghua University)

  • Wanli Liu

    (Tsinghua University)

  • Wenjie Zheng

    (The Ministry of Education Key Laboratory)

Abstract

TNF inhibitors have been used to treat autoimmune and autoinflammatory diseases. Here we report an unexpected mechanism underlying the therapeutic effects of TNF inhibitors in Behçet’s disease (BD), an autoimmune inflammatory disorder. Using serum metabolomics and peripheral immunocyte transcriptomics, we find that polymorphonuclear neutrophil (PMN) from patients with BD (BD-PMN) has dysregulated mevalonate pathway and subsequently increased farnesyl pyrophosphate (FPP) levels. Mechanistically, FPP induces TRPM2-calcium signaling for neutrophil extracellular trap (NET) and proinflammatory cytokine productions, leading to vascular endothelial inflammation and damage. TNF, but not IL-1β, IL-6, IL-18, or IFN-γ, upregulates TRPM2 expression on BD-PMN, while TNF inhibitors have opposite effects. Results from mice with PMN-specific FPP synthetase or TRPM2 deficiency show reduced experimental vasculitis. Meanwhile, analyses of public datasets correlate increased TRPM2 expressions with the clinical benefits of TNF inhibitors. Our results thus implicate FPP-TRPM2-TNF/NETs feedback loops for inflammation aggravation, and novel insights for TNF inhibitor therapies on BD.

Suggested Citation

  • Menghao Zhang & Na Kang & Xin Yu & Xiaoyang Zhang & Qinghui Duan & Xianqiang Ma & Qiancheng Zhao & Zhimian Wang & Xiao’ou Wang & Yeling Liu & Yuxiao Zhang & Can Zhu & Ruiyu Gao & Xin Min & Cuifeng Li , 2024. "TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s disease," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53528-3
    DOI: 10.1038/s41467-024-53528-3
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    References listed on IDEAS

    as
    1. Jing Chen & Xiaochen Zhang & Liping Li & Xianqiang Ma & Chunxiao Yang & Zhaodi Liu & Chenyang Li & Maria J Fernandez-Cabezudo & Basel K al-Ramadi & Chuan Wu & Weishan Huang & Yong Zhang & Yonghui Zhan, 2021. "Farnesyl pyrophosphate is a new danger signal inducing acute cell death," PLOS Biology, Public Library of Science, vol. 19(4), pages 1-25, April.
    2. Arthur Neuberger & Kirill D. Nadezhdin & Alexander I. Sobolevsky, 2021. "Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
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