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

Maria E Moreno-Fernandez; Daniel A Giles; Jarren R Oates; Calvin C Chan; Michelle S M A Damen; Jessica R Doll; Traci E Stankiewicz; Xiaoting Chen; Kashish Chetal; Rebekah Karns; Matthew T Weirauch; Lindsey Romick-Rosendale; Stavra A Xanthakos; Rachel Sheridan; Sara Szabo; Amy S Shah; Michael A Helmrath; Thomas H Inge; Hitesh Deshmukh; Nathan Salomonis; Senad Divanovic

doi:10.1016/j.cmet.2021.04.018

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.

Authors

Maria E Moreno-Fernandez¹, Daniel A Giles¹, Jarren R Oates², Calvin C Chan³, Michelle S M A Damen¹, Jessica R Doll¹, Traci E Stankiewicz¹, Xiaoting Chen⁴, Kashish Chetal⁵, Rebekah Karns⁶, Matthew T Weirauch⁷, Lindsey Romick-Rosendale⁸, Stavra A Xanthakos⁹, Rachel Sheridan¹⁰, Sara Szabo¹⁰, Amy S Shah¹¹, Michael A Helmrath¹², Thomas H Inge¹³, Hitesh Deshmukh¹⁴, Nathan Salomonis⁵, Senad Divanovic¹⁵

Affiliations

¹ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
² Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA.
³ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Medical Scientist Training Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA.
⁴ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; The Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁵ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁶ Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁷ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; The Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁸ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; NMR Metabolomics Core, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁹ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹⁰ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹¹ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹² Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; The Center for Stem Cell & Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹³ Department of Surgery, Children's Hospital Colorado, Aurora, CO 80045, USA.
¹⁴ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; The Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹⁵ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Medical Scientist Training Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; The Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: [email protected].

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 Hormone-Binding Proteins
Thyroid Hormones / immunology*

Substances

CXCR3 protein, human
Carrier Proteins
Membrane Proteins
Receptors, CXCR3
Thyroid Hormones
Pkm protein, mouse
Pyruvate Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding