2. Academic Validation
  3. TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet's disease

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

  • Nat Commun. 2024 Oct 26;15(1):9261. doi: 10.1038/s41467-024-53528-3.
Menghao Zhang # 1,  Na Kang # 2,  Xin Yu # 1,  Xiaoyang Zhang 2,  Qinghui Duan 2,  Xianqiang Ma 3,  Qiancheng Zhao 3,  Zhimian Wang 1,  Xiao'ou Wang 1,  Yeling Liu 1,  Yuxiao Zhang 2,  Can Zhu 2,  Ruiyu Gao 2,  Xin Min 2,  Cuifeng Li 2,  Jin Jin 4,  Qian Cao 5,  Rongbei Liu 5,  Xiaoyin Bai 6,  Hong Yang 6,  Lidan Zhao 1,  Jinjing Liu 1,  Hua Chen 1,  Yonghui Zhang 3,  Wanli Liu 7,  Wenjie Zheng 8
Affiliations

Affiliations

  • 1 Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key Laboratory, Beijing, China.
  • 2 State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
  • 3 School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China.
  • 4 Center for Neuroimmunology and Health Longevity, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 5 Department of gastroenterology & Inflammatory bowel disease Center, Sir Run Run Shaw hospital, school of medicine, Zhejiang University, Hangzhou, China.
  • 6 Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 7 State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China. liulab@tsinghua.edu.cn.
  • 8 Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key Laboratory, Beijing, China. zhengwj@pumch.cn.
  • # Contributed equally.
PMID: 39461948 DOI: 10.1038/s41467-024-53528-3
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.

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