Metabolic skewing in inflammatory hepatic Th17 cells regulates non-alcoholic fatty liver disease (NAFLD) pathogenesis

ABSTRACT: Purpose: To determine the Th17 milleu in the liver during NAFLD in the context of Diet induce obesity Methods: Mice were place on a highfat diet for 20 weeks, Th17 cells were isolated from the liver by FACS sorting the TCRb+CD4+IL-17A-GFP+ cells. Single cells were separated into 6 C1 capture chips and RNA sequencing was performed at an average depth of 3 million paired-end reads (75nt) using the Illumina HiSeq 2500, with SMART-Seq2 version 2 chemistry as recommended by the manufacturer. Results: Here, we demonstrate that NAFLD progression is associated with polarization and accumulation of a unique population of inflammatory hepatic CXCR3+Th17 cells (ihTh17) in mice. Transfer of ihTh17 cells accelerated and exacerbated NAFLD pathogenesis in vivo. Notably, ihTh17 cells, compared to conventional CXCR3-Th17 cells, exhibited increased open chromatin marks in enhancer regions, increased metabolic capacity, and were able to simultaneously produce an array of proinflammatory cytokines which directly contributed to hepatocellular damage. Modulation of the CXCR3-CXCL9/10 axis and ihTh17 metabolic state was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Conclusions: In sum, our data show that the obesity-associated environment regulates Th17 cell competence towards an ihTh17 fate and that the preferential use of glycolytic pathways in ihTh17 cells promotes their inflammatory vigor and contributes to NAFLD progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE138763 | GEO | 2021/10/20

REPOSITORIES: GEO