Pathogenesis Of Obesity-Driven Metabolic Sequelae Is Associated With Th17 Metabolic Switch And Inflammatory Hepatic Th17 Cells

Nonalcoholic fatty liver disease (NAFLD) is a major global health issue. Lack of effective therapies to NAFLD is attributed to limited knowledge of disease etiopathogenesis. Emerging evidence reveal key contribution of the Th17 axis in NAFLD. However, the characteristics and mechanisms underlying the pathogenic potential of Th17 cells in NAFLD remain unknown. Here, we uncover a unique population of inflammatory hepatic CXCR3+Th17 cells (ihTh17) that contribute to NAFLD progression. Longitudinal hepatic accrual of ihTh17 cells correlated with NAFLD severity in mice and was dependent on obesity and CXCR3 axis activation. ihTh17 cells, compared to conventional CXCR3-Th17 cells, exhibited increased open chromatin marks in enhancer regions of inflammatory and metabolic genes, increased glycolytic skewing and metabolic capacity, and were able to simultaneously produce an array of pro inflammatory cytokines that directly promoted hepatocellular damage. Adoptive transfer of ihTh17 cells accelerated and exacerbated NAFLD pathogenesis in vivo. Modulation of the metabolic state of ihTh17 cells was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Importantly, ihTh17 cell hepatic accrual and inflammatory capacity, CXCR3 axis activation, and hepatic expression of glycolysis-associated genes were conserved in humans with NAFLD and positively correlated with disease severity. In sum, we show that the obesity-associated environment regulates Th17 cell metabolism and competence towards a unique inflammatory hepatic Th17 fate in turn contributing to NAFLD progression. Notably, modulation of these pathways holds potential for development of novel therapeutic strategies to NAFLD. Disclosure M.E. Moreno-Fernandez: None. J. Oates: None. M.S. Damen: None. J.R. Doll: None. T.E. Stankiewicz: None. S. Divanovic: Consultant; Self; Janssen Pharmaceuticals, Inc., Pfizer Inc. Funding American Diabetes Association (1-19-PMF-019 to M.E.M-F.); National Institutes of Health (R01DK099222, R01DK099222-02S1P30, DK078392)