Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Is Marked by a Higher Frequency of Th17 Cells in the Liver and an Increased Th17/Resting Regulatory T Cell Ratio in Peripheral Blood and in the Liver

Abstract

Nonalcoholic fatty liver disease is increasing in prevalence. It can be subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Five to twenty percent of cases progress from NAFL to NASH. Increased hepatic Th17 cells and IL-17 expression were observed in NASH mice and patients, respectively. We analyzed CD4+ effector T cells and regulatory T cells (Tregs) from peripheral blood and livers of NAFL and NASH patients. A total of 51 NAFL patients, 30 NASH patients, 31 nonalcoholic fatty liver disease patients (without histology), and 43 healthy controls were included. FACS analysis was performed on PBMCs and intrahepatic lymphocytes. Compared with healthy controls, a lower frequency of resting Tregs (rTregs; CD4+CD45RA+CD25++) and higher frequencies of IFN-γ+ and/or IL-4+ cells were detected among CD4+ T cells of peripheral blood in NASH, and to a lesser degree in NAFL. In hepatic tissue, NAFL to NASH progression was marked by an increase in IL-17+ cells among intrahepatic CD4+ T cells. To define immunological parameters in peripheral blood to distinguish NAFL from NASH, we calculated different ratios. Th17/rTreg and Th2/rTreg ratios were significantly increased in NASH versus NAFL. The relevance of our findings for NASH pathogenesis was highlighted by the normalization of all of the changes 1 y after bariatric surgery. In conclusion, our data indicate that NAFL patients show changes in their immune cell profile compared with healthy controls. NAFL to NASH progression is marked by an increased frequency of IL-17+ cells among intrahepatic CD4+ T cells and higher Th17/rTreg and Th2/rTreg ratios in peripheral blood.

Immune Imbalances in Non-Alcoholic Fatty Liver Disease: From General Biomarkers and Neutrophils to Interleukin-17 Axis Activation and New Therapeutic Targets

“…In a study with 94 subjects (30 with NASH, 31 with NAFLD, and 43 healthy controls), patients with NASH (and in less degree with steatosis) had a lower frequency of T regulatory cells in peripheral blood, in comparison with controls (30). In addition, the progression from steatosis to NASH was marked by a higher frequency of Th17 cells in the liver and an increased Th17/resting T regulatory cell ratio in the liver and in peripheral blood (30). …”

“…NASH and metabolic alterations occurred in mice-fed HFD, and Th17 cells (either AAT or liver-derived) positively correlated with NASH (60). Other studies have shown in parallel that the reduction, dysfunction, or disproportionate number of Treg cells contributes to the progression to NASH because Treg cells play a critical role in regulating the inflammatory processes in the liver (24, 29, 30). This cellular imbalance is accompanied by the activation of the IL-17 axis, and an increase of other pro-inflammatory cytokines such as IL-6, and TNF-α (42, 58); and its value has been highlighted by the demonstration that therapies targeted to reverse this imbalance have shown the potential to alleviate steatosis and the progression to NASH (32, 61, 62).…”

Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells

“…Furthermore, IL-17A−/− mice were resistant to the development of steatohepatitis, whereas wild-type mice showed progression from NAFL to NASH via the induction of IL-17 and downstream mediators [84]. A most recent study reports the progression from NAFL to NASH is marked by an increase of ratio of Th17/resting regulatory T cells (Tregs) in peripheral blood and liver [85]. …”

Clinical Potential of Regulatory T Cell Therapy in Liver Diseases: An Overview and Current Perspectives

“…Reduction in CD4 + CD25 high CD127 low Treg frequency has been described in patients with alcoholic hepatitis (10). Progression from non-alcoholic fatty liver to non-alcoholic steatohepatitis is characterized by a higher frequency of Th17 cells in the liver and an increased ratio of Th17/resting CD4 + CD45RA + CD25 high Treg in peripheral blood (11). We, and others, have reported that there is an increase in Treg frequency in parallel with effector immune cells in autoimmune liver diseases (AILD) (12–15).…”