ABSTRACT
Liver fibrosis is the common response to chronic liver injury, and leads to cirrhosis and its complications. Persistent inflammation is a driving force of liver fibrosis progression. Mucosal-associated invariant T (MAIT) cells are non-conventional T cells that display altered functions during chronic inflammatory diseases. Here, we show that circulating MAIT cells are reduced in patients with alcoholic or non-alcoholic fatty liver disease-related cirrhosis while they accumulate in liver fibrotic septa. Using two models of chronic liver injury, we demonstrate that MAIT cell-enriched mice show increased liver fibrosis and accumulation of hepatic fibrogenic cells, whereas MAIT cell-deficient mice are resistant. Co-culture experiments indicate that MAIT cells enhance the proinflammatory properties of monocyte-derived macrophages, and promote mitogenic and proinflammatory functions of fibrogenic cells, via distinct mechanisms. Our results highlight the profibrogenic functions of MAIT cells and suggest that targeting MAIT cells may constitute an attractive antifibrogenic strategy during chronic liver injury.
Subject(s)
Liver Cirrhosis/immunology , Macrophages/immunology , Mucosal-Associated Invariant T Cells/immunology , Non-alcoholic Fatty Liver Disease/immunology , Adult , Aged , Animals , Cell Count , Cells, Cultured , Coculture Techniques , Female , Humans , Liver/immunology , Liver/pathology , Liver Cirrhosis/blood , Liver Cirrhosis/pathology , Male , Mice , Middle Aged , Non-alcoholic Fatty Liver Disease/blood , Non-alcoholic Fatty Liver Disease/pathologyABSTRACT
Adiponectin levels are reduced in NAFLD patients and genetic variants of adiponectin have been frequently associated with type 2 diabetes and insulin resistance. To determine the genotypic frequencies of adiponectin functional polymorphisms (-11377C/G and +45T/G) and their subsequent effect on disease progression and plasma adiponectin levels in the patients with NAFLD. A total of 137 NAFLD patients and 250 matched controls were enrolled in the study. DNA sequencing and genotyping were performed to identify the genetic variants. The plasma adiponectin levels were assessed by ELISA. Homozygous mutant genotype of adiponectin SNPs, -11377C/G and +45T/G, were significantly more prevalent in NAFLD patients than controls (Bonferroni corrected p=0.014 and 0.018, respectively). Plasma adiponectin levels were significantly lower in the NAFLD patients as compared to controls. Moreover, presence of 'G' allele at position -11377C/G and +45T/G was found to be associated with necroinflammatory grade and reduced adiponectin levels, (p values 0.02 and 0.01) respectively. -11377G and +45G alleles are associated with severity of liver disease and hypoadiponectemia, in the patients with NAFLD, respectively.