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, Wenjie Zheng
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. TNF inhibitors show clinical benefits for Behçet’s disease (BD), but the underlying molecular insights are still unclear. Here the authors use both patient samples and mouse genetic models to show that TNF inhibitors may target a metabolite/TRPM2/calcium signaling positive feedback loop of inflammation amplification for dampening vasculitis in BD.