The Metabolite

Recent studies have identified certain metabolites, released during metabolic pattern changes in immune progression, as a new type of endogenous damage signal to excessively activate the innate immune system and cause inflammatory injury. Farnesyl pyrophosphate (FPP) is a metabolite of the mevalonate (MVA) pathway (the cholesterol synthesis imitation pathway).

The Disease

Behçet’s disease (BD) is a representative systemic vasculitis with aberrant and excessive activation of both innate and adaptive immunity, and is thus considered as a crucial clinical condition linking both autoimmunity and autoinflammation. Zheng’s Lab, a team of the authors focused on BD research for over 10 years, as well as other researchers, have identified pathogenetic roles of endogenous damage signals in BD, which aggravate inflammation with overproduction of TNF-α, IFN-γ, and IL-6. Hence, BD is ideal as a representative disease to investigate the mechanism of action underlying the therapeutic effects of TNF inhibitors.

The immunometabolic pathogenesis of BD is currently limited. Here, by systematically screening serum metabolites and metabolic changes in peripheral blood immune cells based on previous multi-omics research from Zheng’s Lab, the studies discovered an aberrant MVA pathway in BD polymorphonuclear neutrophil (PMN), and overexpression of its metabolite FPP in BD serum and PMNs. With the collaboration between Zheng’s lab and Liu’s lab, the study illustrates that FPP induces TRPM2-calcium signaling for neutrophil extracellular trap (NET) and proinflammatory cytokine production, leading to vascular endothelial inflammation and damage.

The Drug

Specifically, this study elucidates that TNF upregulates TRPM2 expression on BD-PMN, while TNF inhibitors have an opposite effect, highlighting a novel mechanism underlying its therapeutic benefits. Results from mice with PMN-specific FPP synthetase or TRPM2 deficiency demonstrated reduced experimental vasculitis, supporting the involvement of FPP and TRPM2 in neutrophil hyperactivation and vascular endothelial inflammation and damage.

In addition, analyses of publicly available datasets correlate increased TRPM2 expression with the clinical benefit of TNF inhibitors in several autoimmune and autoinflammatory diseases, extending the implications beyond BD.

Conclusion

This study is a significant step forward in the understanding of BD, which reveals metabolic involvements of BD pathogenesis and sheds light on a novel therapeutic mechanism of TNF inhibitors. By targeting the critical metabolic mechanisms, we may be able to develop more effective therapies for BD and potentially other autoimmune/autoinflammatory diseases.