The chemokine fractalkine (C–X3–C motif chemokine ligand 1, CX 3 CL1) and its receptor (C–X3–C motif chemokine receptor 1, CX 3 CR1) are known to mediate leukocyte chemotaxis, adhesion, and survival. In the liver, CX 3 CR1 is expressed on multiple cell types including monocytes and dendritic cells. However, the function of CX 3 CR1 on hepatic dendritic cells (HDCs) is still poorly understood. In the present study, we investigated the role of CX 3 CR1 on mouse HDCs during homeostasis and following acute liver injury. At homeostasis, CX 3 CR1 expression was detected amongst CD11b + /CD103 − type 2 myeloid HDCs (mHDCs) and these cells were characterized by the production of interleukin-10 (IL-10). Mice treatment with the hepatotoxic agent carbon tetrachloride (CCl 4 ) up-regulated liver IL-10 expression and stimulated the expansion of CX 3 CR1 + mHDCs which also showed a more mature phenotype. The absence of CX 3 CR1 in naïve CX 3 CR1 gfp/gfp mice specifically reduced the CD11b + /IL-10 + mHDCs as compared with CX 3 CR1-proficient animals (CX 3 CR1 +/gfp ). Following CCl 4 poisoning, the liver recruitment and maturation of CD11b + mHDCs was significantly attenuated in CX 3 CR1 gfp/gfp mice. Furthermore, these mice suffered more severe hepatic injury and inflammation than CX 3 CR1 +/gfp mice and showed a delated recovery from liver damage. Such a worsening of liver injury in CX 3 CR1 gfp/gfp mice was associated with an impaired up-regulation of hepatic IL-10 expression and a lower number of IL-10 producing CD11b + mHDCs. Consistently, IL-10 inactivation enhanced hepatic injury and inflammation in CX3CR1 +/gfp mice receiving CCl 4 . Altogether, these data indicate a novel role of the CX 3 CL1/CX 3 CR1 axis in liver type 2 mHDC functions, pointing out the importance of CX 3 CR1 in promoting IL-10-mediated anti-inflammatory actions of HDCs.

Background: Dysregulation of miRNAs has been described in tissue and serum from patients with acute and chronic liver diseases. However, only little information on the role of miR-223 in the pathophysiology of acute liver failure (ALF) and liver cirrhosis is available. Methods: We analysed cell and tissue specific expression levels as well as serum concentrations of miR-223 in mouse models of acute (hepatic ischaemia and reperfusion, single CCl 4 injection) and chronic (repetitive CCl 4 injection, bile duct ligation (BDL)) liver diseases. Results were validated in patients and correlated with clinical data. The specific hepatic role of miR-223 was analysed by using miR-223 −/ − mice in these models. Results: miR-223 expression was significantly dysregulated in livers from mice after induction of acute liver injury and liver fibrosis as well as in liver samples from patients with ALF or liver cirrhosis. In acute and chronic models, hepatic miR-223 up-regulation was restricted to hepatocytes and correlated with degree of liver injury and hepatic cell death. Moreover, elevated miR-223 expression was reflected by significantly higher serum levels of miR-223 during acute liver injury. However, functional in vitro and in vivo experiments revealed no differences in the degree of liver cell death and liver fibrosis as miR-223 −/− mice behaved identical with wild-type ( wt ) mice in all tested models. Conclusion: miR-223 represents a promising diagnostic marker in a panel of serum markers of liver injury. Together with previously published data, our results highlight that the role of miR-223 in the pathophysiology of the liver is complex and needs further analysis.

miR-192-5p has gained increasing relevance in various diseases, however, its function in acute liver injury is currently unknown. We analysed miR-192-5p serum levels and hepatic miR-192-5p expression in mice after hepatic ischaemia and reperfusion (I/R) as well as in toxic liver injury. On a functional level, miRNA levels were analysed in the different hepatic cell-compartments and in the context of tumour necrosis factor (TNF)-dependent liver cell death. We detected increased serum levels of miR-192-5p after hepatic I/R- and carbon tetrachloride (CCl 4 )-induced liver injury. miR-192-5p levels correlated with the degree of liver damage and the presence of hepatic cell death detected by TUNEL stainings (terminal deoxynucleotidyltransferase-mediated dUTP biotin nick-end labelling stainings). Moreover, expression of miR-192-5p was increased in a hypoxia/reoxygenation (H/R) model of in vitro hepatocyte injury, supporting that the passive release of miR-192-5p represents a surrogate for hepatocyte death in liver injury. In critically ill patients, miR-192-5p levels were elevated selectively in patients with liver injury and closely correlated with the presence of hepatic injury. In contrast with up-regulated miR-192-5p in the serum, we detected a down-regulation of miR-192-5p in both injured mouse and human livers. Deregulation of miR-192-5p in livers was dependent on stimulation with TNF. Functional experiments confirmed a protective effect of down-regulation of miR-192-5p in hepatocytes, suggesting a role of miR-192-5p in limiting liver injury. Finally, we identified Zeb2, an important regulator of cell death, as a potential target gene mediating the function of miR-192-5p . Our data suggest that miR-192-5p is involved in the regulation of liver cell death during acute liver injury and might represent a potent marker of hepatic injury.