PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease

Cell Metab. 2021 Jun 1;33(6):1187-1204.e9. doi: 10.1016/j.cmet.2021.04.018. Epub 2021 May 17.

Abstract

Emerging evidence suggests a key contribution to non-alcoholic fatty liver disease (NAFLD) pathogenesis by Th17 cells. The pathogenic characteristics and mechanisms of hepatic Th17 cells, however, remain unknown. Here, we uncover and characterize a distinct population of inflammatory hepatic CXCR3+Th17 (ihTh17) cells sufficient to exacerbate NAFLD pathogenesis. Hepatic ihTh17 cell accrual was dependent on the liver microenvironment and CXCR3 axis activation. Mechanistically, the pathogenic potential of ihTh17 cells correlated with increased chromatin accessibility, glycolytic output, and concomitant production of IL-17A, IFNγ, and TNFα. Modulation of glycolysis using 2-DG or cell-specific PKM2 deletion was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Importantly, ihTh17 cell characteristics, CXCR3 axis activation, and hepatic expression of glycolytic genes were conserved in human NAFLD. Together, our data show that the steatotic liver microenvironment regulates Th17 cell accrual, metabolism, and competence toward an ihTh17 fate. Modulation of these pathways holds potential for development of novel therapeutic strategies for NAFLD.

Keywords: CXCR3; IFNγ; NAFLD; PKM; T cell; TNF; cellular metabolism; glycolysis; liver; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / immunology*
  • Cell Line
  • Female
  • Humans
  • Male
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / immunology*
  • Pyruvate Kinase / immunology*
  • Receptors, CXCR3 / immunology*
  • Th17 Cells / cytology
  • Th17 Cells / immunology*
  • Thyroid Hormones / immunology*

Substances

  • CXCR3 protein, human
  • Carrier Proteins
  • Membrane Proteins
  • Receptors, CXCR3
  • Thyroid Hormones
  • thyroid hormone-binding proteins
  • Pkm protein, mouse
  • Pyruvate Kinase