Hepatic natural killer T‐cell and CD8+ T‐cell signatures in mice with nonalcoholic steatohepatitis

Abstract

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.

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

“…In mice and humans, cytotoxic CD8+ T cells accumulate in the liver during NAFLD, and their pharmacologic or genetic ablation results in decreased steatosis, IR, inflammation, and hepatic stellate cell activation. Activation of these cytotoxic CD8+ T cells is supported by type I IFN responses and leads to the production of the proinflammatory cytokines IFNγ and TNFα .…”

Autoimmune responses and inflammation in type 2 diabetes

“…Adipose tissue lipolysis has been shown to lead to lipid accumulation in liver and thus contributes to hepatic insulin resistance via dampening of the insulin signaling pathway 27,79 . Pathogenic CD8 + T cells have also shown to accumulate in the liver during diet‐induced obesity and are activated by IFNα in the liver 80‐82 . A recent study highlighted the role of CD40‐expressing CD11c + DCs in the liver in obesity‐induced insulin resistance.…”

The Role of Innate Immune Cells in Nonalcoholic Steatohepatitis

“…Conversely, once stimulated, ILC2s secrete IL‐13 and IL‐4, which activate HSCs and stimulate LF. More recently, innate‐like T lymphocytes, which include iNKT cells and MAIT cells, have emerged as accelerators of inflammation and fibrosis during CCL 4 ‐ or BDL‐induced liver injury . However, the definitive roles played by these innate‐like lymphocytes in the pathogenesis of NASH remain unknown.…”