5-Hydroxyndole-3-acetic acid suppresses activation of glutamate oxaloacetate transaminase 1 linked to Th1/17 cell differentiation and ameliorates rheumatoid arthritis

Abstract

Abstract It has been established that cell proliferation and survival activities can be controlled according to metabolic resources in inflammation. However, it is not clear how T cell-mediated inflammatory immune responses in rheumatoid arthritis (RA) affect the activity and regulation of inflammatory cells by meeting biosynthesis and bioenergy requirements. This study evaluated the effect of serotonin-derived metabolite 5-Hydroxyndole-3-acetic acid (5-HIAA) on the increase in glutamate oxaloacetate transaminase 1 (GOT1) by the differentiation of Th1, Th17, or Th1/17 cells. The differentiation of Th1, Th17, or Th1/17 cells increased GOT1 and showed that GOT1 promotes the differentiation of Th1, Th17, or Th1/17 cells. Conversely, selective inhibition of GOT1 using 5-HIAA blocked the differentiation of Th1, Th17, or Th1/17 cells. Furthermore, inhibition of GOT1 using 5-HIAA ameliorated RA through up-regulation of regulatory T cells (Foxp3+CD4+), suppression of pro-inflammatory cytokines, and inhibition of Th1/17 responses in mouse joints. Therefore, targeting glutamate-dependent metabolic pathways would be an effective therapeutic strategy for rheumatoid arthritis and a wide spectrum of autoimmune diseases. Supported by 21st Century Medical Science Creative Human Resource Development Center