Hepatic
inflammation is a key pathological feature of
Nonalcoholic Steatohepatitis (NASH). Natural Killer T-cells (NKT) and CD8+ T-cells are known to play an important role in
obesity related adipose tissue
inflammation. We hypothesized that these same inflammatory phenotypes would be present in progressive NASH. We used a previously established high fat high
carbohydrate (HFHC) murine obesogenic diet model of progressive NASH to investigate the role of NKT cells and CD8+ T-cells in C57Bl6/J mice. Further, to better understand the impact of these cell populations; CD1d-deficient and CD8+ T-cell depleted mice were subjected to HFHC diet for 16 weeks. C57Bl6/J mice fed HFHC diet had increased
body weight, liver
triglyceride content, serum
alanine aminotransferase (ALT) levels and increased NKT cells and CD8+ T-cells infiltration in the liver. In addition human liver sections from patients with NASH showed increased CD8+ T-cells. In comparison, CD1d-deficient and CD8-T cell depleted mice fed HFHC had lower hepatic
triglyceride content, lower ALT levels, as well reduced α-smooth muscle actin (αSMA),
collagen type 1 alpha 1 (Col1a1),
collagen type 1 alpha 2 (
Col1a2)
mRNA expression, lower activated resident macrophages and infiltrating macrophages and improved
NAFLD activity scores. Further, while CD1d-deficient mice were protected against
weight gain on the HFHC diet, CD8 T-cell depleted mice gained weight on the HFHC diet.
CONCLUSION: We found that NASH has an immunological signature that includes hepatic infiltrating NKT and CD8+ T-Cells. Depletion of these cells resulted in reduced NASH progression and thus presents novel therapeutic avenues for the treatment of NASH.