Inhibition of Glycolysis in Pathogenic TH17 Cells through Targeting a <i>miR-21–Peli1</i>–c-Rel Pathway Prevents Autoimmunity

Abstract

It is well known that some pathogenic cells have enhanced glycolysis; the regulatory network leading to increased glycolysis are not well characterized. In this study, we show that CNS-infiltrated pathogenic T_H17 cells from diseased mice specifically upregulate glycolytic pathway genes compared with homeostatic intestinal T_H17 cells. Bioenergetic assay and metabolomics analyses indicate that in vitro-derived pathogenic T_H17 cells are highly glycolytic compared with nonpathogenic T_H17 cells. Chromatin landscape analyses demonstrate T_H17 cells in vivo that show distinct chromatin states, and pathogenic T_H17 cells show enhanced chromatin accessibility at glycolytic genes with NF-κB binding sites. Mechanistic studies reveal that <i>miR-21</i> targets the E3 ubiquitin ligase <i>Peli1</i>-c-Rel pathway to promote glucose metabolism of pathogenic T_H17 cells. Therapeutic targeting c-Rel-mediated glycolysis in pathogenic T_H17 cells represses autoimmune diseases. These findings extend our understanding of the regulation T_H17 cell glycolysis in vivo and provide insights for future therapeutic intervention to T_H17 cell-mediated autoimmune diseases.