TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s disease
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.
Authors
- Lidan Zhao (ORCID: https://orcid.org/0000-0001-6599-3339)
- Wenjie Zheng (ORCID: https://orcid.org/0000-0002-3165-8185)
- Xiaoyin Bai (ORCID: https://orcid.org/0000-0002-9092-7592)
- Rongbei Liu (ORCID: https://orcid.org/0000-0002-8667-8474)
- Xin Min (ORCID: https://orcid.org/0000-0003-3953-2699)
- Zhimian Wang
- Qinghui Duan (ORCID: https://orcid.org/0000-0001-6457-9777)
- Yeling Liu
- Cuifeng Li
- Na Kang (ORCID: https://orcid.org/0000-0003-4771-0475)
- Hong Yang (ORCID: https://orcid.org/0000-0002-2986-7324)
- Xiaoyang Zhang (ORCID: https://orcid.org/0000-0002-0031-0290)
- Yonghui Zhang (ORCID: https://orcid.org/0000-0002-9842-3049)
- Hua Chen (ORCID: https://orcid.org/0000-0003-4323-6403)
- Wanli Liu (ORCID: https://orcid.org/0000-0003-0395-2800)
- Jin Jin (ORCID: https://orcid.org/0000-0001-7887-5972)
- Jinjing Liu (ORCID: https://orcid.org/0000-0003-2150-7540)
- Yuxiao Zhang (ORCID: https://orcid.org/0000-0002-1690-4683)
- Qiancheng Zhao (ORCID: https://orcid.org/0000-0003-3134-4159)
- Xin Yu (ORCID: https://orcid.org/0000-0002-5446-0120)
- Qian Cao (ORCID: https://orcid.org/0000-0001-7938-7532)
- Can Zhu (ORCID: https://orcid.org/0009-0008-2623-6974)
- Xianqiang Ma
- Ruiyu Gao
- Xiao'ou Wang
- Menghao Zhang (ORCID: https://orcid.org/0009-0002-5481-6390)
Institutions
- Sun Yat-sen University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking Union Medical College Hospital (CN)
- Sir Run Run Shaw Hospital (CN)
- King Center (US)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- Beijing Tsinghua Chang Gung Hospital (CN)
- Center for Life Sciences (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-26
- DOI
- https://doi.org/10.1038/s41467-024-53528-3
- Citations
- 12
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- National Natural Science Foundation of China
- Tsinghua University
- Peking Union Medical College Hospital
- Peking Union Medical College
- Fundamental Research Funds for the Central Universities