The oncometabolite R-2-hydroxyglutarate inhibits microglia activation via FTO/NF-B pathway

Lu Wang¹Xifeng Jing¹Huiting Zhang¹Yuanchi Huang¹Yuxin Kang¹Yulan Qian^2,3*Dong Chen^1*

• ¹Hematology Center, Cyrus Tang Medical institute, Soochow University, Suzhou, China
• ²Department of Pharmacy, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
• ³MOE Engineering Center of Hematological Disease, Soochow University, Suzhou, China

(R)-2-hydroxyglutarate (R-2HG), generated by the isocitrate dehydrogenase 1 mutations (mIDH1), inhibits a variety of-ketoglutarate-dependent enzymes and is an oncometabolite that promotes tumorigenesis through epigenetic alterations. Microglia are considered to be the resident macrophages in the brain and the major immune cell population in gliomas, playing a key role in the development of gliomas. Although R-2HG was reported to impair CD8+ T cell function and suppress antitumor T cell immunity, its role in microglia activation remains unknown. Here, we investigated the effect of R-2HG on microglia inflammatory activation. BV2 cells treated with glioma conditioned medium (CM) showed significant cytokines increasement, while R-2HG specifically inhibited the activation of IL-6. Mechanistically, R-2HG significantly inhibited CM-induced phosphorylation of IB and p65, leading to impaired nuclear translocation of the p65. Moreover, the -KG addition abolished the inhibitory effect of R-2HG on IL-6 activation. Further investigation demonstrated that R-2HG specifically down-regulated IL-6 expression by inhibiting FTO activity. Collectively, we found that R-2HG inhibits microglia activation by regulating the FTO/NF-B signaling pathway and may be benefit for exploring the mechanism of antitumor immunity in IDH mutant gliomas.