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

Abstract

Non-alcoholic fatty liver disease (NAFLD) is an increasing problem worldwide and is associated with negative outcomes such as cirrhosis, hepatocellular carcinoma, insulin resistance, diabetes, and cardiovascular events. Current evidence shows that the immune response has an important participation driving the initiation, maintenance, and progression of the disease. So, various immune imbalances, from cellular to cytokines levels, have been studied, either for better compression of the disease pathophysiology or as biomarkers for severity assessment and outcome prediction. In this article, we performed a thorough review of studies that evaluated the role of inflammatory/immune imbalances in the NAFLD. At the cellular level, we gave special focus on the imbalance between neutrophils and lymphocytes counts (the neutrophil-to-lymphocyte ratio), and that which occurs between T helper 17 (Th17) and regulatory T cells as emerging biomarkers. By extension, we reviewed the reflection of these imbalances at the molecular level through pro-inflammatory cytokines including those involved in Th17 differentiation (IL-6, IL-21, IL-23, and transforming growth factor-beta), and those released by Th17 cells (IL-17A, IL-17F, IL-21, and IL-22). We gave particular attention to the role of IL-17, either produced by Th17 cells or neutrophils, in fibrogenesis and steatohepatitis. Finally, we reviewed the potential of these pathways as new therapeutic targets in NAFLD.

WITHDRAWN: Ginkgolide B reduces hepatic lipid accumulation and ameliorates nonalcoholic fatty liver disease in high-fat diet–induced obese mice

“…Obesity increases de novo lipogenesis, inducing hepatic steatosis and NAFLD [12]. Excessive lipid accumulation in the hepatic tissue obstructs the normal physiological function of hepatocytes, and induced insulin resistance, inflammation, and peroxidation can cause the development of chronic liver fibrosis and hepatic cancer [22,23]. Many studies have found that reducing lipid accumulation can decrease liver inflammation and fibrosis in NAFLD, even allowing for the possibility of a return to normal liver function and lipogenesis, (B) the Sirt-1/AMPK pathway, and (C) lipolysis-and β-oxidation-associated proteins detected by western blot.…”

Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice

“…Hepatic accumulation of neutrophils, macrophages, and CD4 1 T cells (e.g., T helper [Th]1 and Th17 subsets) correlates with NAFLD progression. (34,35) NOX2 regulates hepatic immune cell infiltration and immune cell cytokine production. (36) Notably, proinflammatory cytokines (e.g., IFN-c, TNF-a, IL-17A) are well-established modulators of NAFLD pathogenesis.…”

Nonalcoholic fatty liver disease promotes hepatocellular carcinoma through direct and indirect effects on hepatocytes

“…Our group discovered that peripheral blood Th17 cells from HCC patients suppress CD8 + T-cell responses indicating that Th17 cells promote HCC [80]. Accumulation of Th17 cells in NAFLD liver has been repeatedly observed [81][82][83][84]. In patients, the progression from NAFLD to NASH is marked by an increase in intrahepatic Th17 cells [84].…”