Abstract
Non-alcoholic fatty liver disease (NAFLD) has been on a global rise. While animal models have rendered valuable insights to the pathogenesis of NAFLD, discrepancy with patient data still exists. Since non-alcoholic steatohepatitis (NASH) involves chronic inflammation, and CD4+ T cell infiltration of the liver is characteristic of NASH patients, we established and characterized a humanized mouse model to identify human-specific immune response(s) associated with NAFLD progression. Immunodeficient mice engrafted with human immune cells (HIL mice) were fed with high fat and high calorie (HFHC) or chow diet for 20 weeks. Liver histology and immune profile of HIL mice were analyzed and compared with patient data. HIL mice on HFHC diet developed steatosis, inflammation and fibrosis of the liver. Human CD4+ central and effector memory T cells increased within the liver and in the peripheral blood of our HIL mice, accompanied by marked up-regulation of pro-inflammatory cytokines (IL-17A and IFNγ). In vivo depletion of human CD4+ T cells in HIL mice reduced liver inflammation and fibrosis, but not steatosis. Our results highlight CD4+ memory T cell subsets as important drivers of NAFLD progression from steatosis to fibrosis and provides a humanized mouse model for pre-clinical evaluation of potential therapeutics.
Highlights
Over the past few decades, the prevalence of non-alcoholic fatty liver disease (NAFLD) – an array of progressive clinical presentations including non-alcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis, liver failure, and hepatocellular carcinoma (HCC) – has increased substantially, surpassing other liver conditions as the leading cause of liverrelated morbidity and mortality [1]
Analysis of liver sections revealed centrilobular macrovesicular and microvesicular steatosis, periportal and/or lobular infiltration of immune cells, and perisinusoidal and periportal fibrosis corresponding to stage 2 fibrosis in human NASH [21], collectively leading to an overall higher NAFLD score in high fat and high calorie (HFHC)-fed compared to chow-fed HIL mice (Figures 1C,D)
We found activated hepatic stellate cells in fibrotic areas suggesting their involvement in liver fibrosis (Figure 1F)
Summary
Over the past few decades, the prevalence of non-alcoholic fatty liver disease (NAFLD) – an array of progressive clinical presentations including non-alcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis, liver failure, and hepatocellular carcinoma (HCC) – has increased substantially, surpassing other liver conditions (e.g., viral hepatitis and alcoholic liver disease) as the leading cause of liverrelated morbidity and mortality [1]. NASH is irreversible and potentially fatal as it increases the risks of cirrhosis, liver failure, and HCC [5]. The pathogenesis of NAFLD is not fully elucidated but is hypothesized to occur through a “multi-hit” manner. It begins with lipid accumulation in hepatocytes. Disease progression beyond NAFL (i.e., NASH, fibrosis, etc.) has been shown to be promoted by the generation of hepatic reactive oxygen species (ROS), macrophage activation, transforming growth factor beta 1 (TGF-β1)-mediated collagen deposition, imbalance between Th17 and regulatory T cells (Treg), and metabolic activation of intrahepatic CD8+ T cells and natural killer T cells (NK-T) [6, 7]
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