Abstract
Fulminant hepatic failure (FHF) is defined as rapid acute liver injury, often complicated with spontaneous bacterial peritonitis (SBP). The precise onset of FHF with SBP is still unknown, but it is thought that SBP closely correlates with a weakened intestinal barrier. Dendritic cells (DCs) play a crucial role in forming the intestinal immune barrier, therefore the number, maturity and chemotactic ability of intestinal DCs were studied in FHF. Mouse intestinal and spleen DCs were isolated by magnetic-activated cell sorting (MACS) and surface markers of DCs, namely CD11c, CD74, CD83 and CD86, were identified using flow cytometry. Immunohistochemistry and Western blotting were performed to detect the distribution and expression of CC-chemokine receptor 7 (CCR7) and CC-chemokine receptor 9 (CCR9), as well as their ligands-CC-chemokine ligand 21 (CCL21) and CC-chemokine ligand 25 (CCL25). Real-time PCR was used to detect CCR7 and CCR9 mRNA, along with their ligands-CCL21 and CCL25 mRNA. Flow cytometry analysis showed that the markers CD74, CD83 and CD86 of CD11c+DCs were lower in the D-galactosamine (D-GalN) group and were significantly decreased in the FHF group, while there were no significant changes in the expression of these markers in the lipopolysaccharide (LPS) group. Immunohistochemistry results showed that staining for CCR7 and CCR9, as well as their ligands CCL21 and CCL25, was significantly weaker in the D-GalN and FHF groups compared with the normal saline (NS) group or the LPS group; the FHF group even showed completely unstained parts. Protein expression of CCR7 and CCR9, as well as their ligands- CCL21 and CCL25, was also lower in the D-GalN group and decreased even more significantly in the FHF group. At the gene level, CCR7 and CCR9, along with CCL21 and CCL25 mRNA expression, was lower in the D-GalN group and significantly decreased in the FHF group compared to the NS and LPS groups, consisting with the protein expression. Our study indicated that intestinal DCs were decreased in number, maturity and chemotactic ability in FHF and might contribute to a decreased function of the intestinal immune barrier in FHF.
Highlights
Fulminant hepatic failure (FHF) refers to sudden necrosis of liver cells and fast deterioration of liver functions
We recently showed that CD11b/c, CD83, CD86 and the MHCII-associated invariant chain Ii, the T cell marker (CD3), and AKT/phosphorylated-AKT (p-AKT) were significantly altered in FHF[13]
Results demonstrated (Fig 2) that CD74, CD83 and CD86 of spleen CD11c+Dendritic cells (DCs) were lower in the D-GalN group and significantly lower in the FHF group (p
Summary
Fulminant hepatic failure (FHF) refers to sudden necrosis of liver cells and fast deterioration of liver functions. Increased bacterial translocation from the intestine caused by portal hypertension [2], and small-intestinal bacterial overgrowth (SIBO) is highly prevalent in patients with cirrhosis [3]. Decreased intestinal barrier functions have been proved in animal models and humans in advanced liver disease [5, 6]. DCs upregulate MHC and costimulatory molecules at the cell surface to downregulate phagocytic activity while increase processing capacity[9]. CC-chemokine receptor 9 (CCR9) is another candidate chemokine receptor for the regulation of DCs trafficking; the interaction between CCR9 and its ligand CCL25 contributes to the migration of T cells and DCs into the small intestine and movement of T cells in the thymus [12]
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