# Genetic ablation of interleukin-17A augments fibrosis in a mouse model of cholestatic liver injury

## TL;DR

Removing IL-17A in mice worsens liver fibrosis, suggesting it normally limits harmful fibrogenic signals like LIGHT from immune cells.

## Contribution

Shows IL-17A limits LIGHT expression in Th1 CD4+ T cells, linking it to reduced fibrosis in cholestatic liver injury.

## Key findings

- Il-17a-/- mice had increased fibrosis and more myofibroblasts compared to wild-type mice.
- LIGHT expression was upregulated in Th1 CD4+ T cells of Il-17a-/- mice and activated hepatic stellate cells in vitro.
- LIGHT expression was not found in myeloid cells but was specific to CD4+ T cells.

## Abstract

The underlying mechanisms contributing to cholestatic liver injury remain unclear. The pro-inflammatory leukocyte-restricted cytokine interleukin-17A (IL-17A) has been implicated in human cholestatic liver injury. However, mechanistic insights are lacking and require further exploration in preclinical models. Herein, we examined the effect of IL-17A genetic ablation in a mouse model of cholestatic liver injury.

Age and gender-matched littermate wild type (WT) and Il-17a-/- C57BL/6 mice were fed an intermittent 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 21 days to induce cholestatic liver injury or a control diet.

As compared to WT littermates, Il-17a-/- mice displayed more abundant desmin-positive myofibroblasts and increased fibrosis. NanoString analysis of intrahepatic leukocyte populations using a fibrosis-related gene panel identified upregulation of Tnfsf14 (encoding the protein LIGHT) in the DDC-fed Il-17a-/- mice. Although mass cytometry identified an increase in myeloid cells in both genotypes of the DDC-fed mice, we could not identify LIGHT expression in this cell lineage. Instead, the upregulation of LIGHT expression was largely restricted to a CD4+ T cell population as assessed by flow cytometry. Enhanced LIGHT expression was observed in a Th1+ CD4+ T cell population. LIGHT activated primary human hepatic stellate cells in vitro, suggesting that LIGHT stimulation of hepatic fibrogenesis may be direct.

Taken together, these data suggest that IL-17A restrains expression of the profibrogenic cytokine, LIGHT, by Th1-polarized CD4+ T cells, and implicate a role for LIGHT in cholestatic fibrogenesis in DDC-fed mice; a finding which requires validation in additional models.