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

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, Jin Jin, Qian Cao, Rongbei Liu, Xiaoyin Bai, Hong Yang, Lidan Zhao, Jinjing Liu, Hua Chen, Yonghui Zhang, Wanli Liu () and Wenjie Zheng ()
Additional contact information
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

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-53528-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53528-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-53528-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().