# Immunopathogenesis of non-alcoholic fatty liver disease

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $67,836

## Abstract

SUMMARY
The unabated obesity pandemic drives dramatic increases in the incidence of common metabolic derangements
including non-alchoholic fatty liver disease (NAFLD). The immune system provides a critical causative link
between obesity and NAFLD pathogenesis. Activation of the interleukin (IL) 17 axis is a key contributor to NAFLD
progression. Given the therapeutic promise for targeting pathogenic immune responses in NAFLD, enhanced
understanding of the cellular and molecular mechanisms underlying IL-17 axis-dependent pathogenicity is a high
priority. In NAFLD, Th17 cells are the primary hepatic producers of IL-17A. Although Th17 cell heterogeneity is
a known determinant of inflammatory disease severity, exclusive cellular characteristics and function of hepatic
Th17 cells in NAFLD have not been studied. Here, we demonstrate that NAFLD progression correlates with
accrual of a unique inflammatory hepatic Th17 cell subset (ihTh17) that exhibits metabolic, epigenetic, and
transcriptional signatures distinct from the conventional hepatic Th17 cells (chTh17) and from the inflammatory
Th17 cells observed in mouse models of EAE and Crohn’s disease. Our exciting preliminary data, in mice, further
suggest that: (i) obesity-associated microbiome regulates ihTh17 cell activation; (ii) the CXCR3 axis regulates
ihTh17-induced NAFLD pathogenesis; and (iii) ihTh17 cells are sufficient to exacerbate NAFLD progression
above the level induced by chTh17 cells. Importantly, these findings are recapitulated in human disease where
NASH patients exhibit increased CXCR3 axis activation and hepatic infiltration of ihTh17 cells. Together, our
findings and existing literature strongly support the central hypothesis that obesity-driven hepatic accrual of
ihTh17 cells is critical to the pathogenesis of NAFLD. Our overaching hypothesis will be tested via intently
designed aims that will: (1) Determine the factors contributing to ihTh17 emergence in NAFLD; (2) Determine
the contribution of the CXCR3 axis to ihTh17 hepatic accrual in NAFLD; and (3) Determine the contribution of
cellular metabolism to ihTh17 inflammatory vigor and NAFLD pathogenesis. Mechanistic hypotheses associated
with these aims, respectively, are: (a) the obesity-associated inflammatory and microbiome environment shape
the emergence of ihTh17 cell phenotype; (b) CXCR3 expression by ihTh17 cells and CXCL10 expression by
hepatocytes promotes ihTh17 hepatic accrual; and (c) PKM2-driven glycolysis fuels ihTh17 cytokine production
and exacerbates NAFLD pathogenesis. Thus, our proposed studies will provide new knowledge into previously
unexplored cellular and molecular processes licensing ihTh17 pathogenic potential in experimental NAFLD and
the extent of their involvement in human disease. As therapies to NAFLD are lacking, new insights to IL-17 axis-
dependent pathogenic mechanisms hold potential for discovery of novel predictive, preventive and therapeutic
avenues.

## Key facts

- **NIH application ID:** 10427752
- **Project number:** 3R01DK099222-08S1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Senad Divanovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $67,836
- **Award type:** 3
- **Project period:** 2013-09-05 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427752

## Citation

> US National Institutes of Health, RePORTER application 10427752, Immunopathogenesis of non-alcoholic fatty liver disease (3R01DK099222-08S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10427752. Licensed CC0.

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