Inducible T-Cell Costimulator Mediates Lymphocyte/Macrophage Interactions During Liver Repair
Naresh Naik Ramavath, Laila Lavanya Gadipudi, Alessia Provera, Casimiro Luca Gigliotti, Elena Boggio, Cristina Bozzola, Emanuele Albano, Umberto Dianzani, Salvatore Sutti
Abstract
The liver capacity to recover from acute liver injury is a critical factor in the development of acute liver failure (ALF) caused by viral infections, ischemia/reperfusion or drug toxicity. Liver healing requires the switching of pro-inflammatory monocyte-derived macrophages(MoMFs) to a reparative phenotype. However, the mechanisms involved are still incompletely characterized. In this study we investigated the contribution of T-lymphocyte/macrophage interaction through the co-stimulatory molecule Inducible T-cell co-stimulator (ICOS; CD278) and its ligand (ICOSL; CD275) in modulating liver repair. The role of ICOS/ICOSL dyad was investigated during the recovery from acute liver damage induced by a single dose of carbon tetrachloride (CCl 4 ). Flow cytometry of non-parenchymal liver cells obtained from CCl 4 -treated wild-type mice revealed that the recovery from acute liver injury associated with a specific up-regulation of ICOS in CD8 + T-lymphocytes and with an increase in ICOSL expression involving CD11b high /F4-80 + hepatic MoMFs. Although ICOS deficiency did not influence the severity of liver damage and the evolution of inflammation, CCl 4 -treated ICOS knockout (ICOS -/- ) mice showed delayed clearance of liver necrosis and increased mortality. These animals were also characterized by a significant reduction of hepatic reparative MoMFs due to an increased rate of cell apoptosis. An impaired liver healing and loss of reparative MoMFs was similarly evident in ICOSL-deficient mice or following CD8 + T-cells ablation in wild-type mice. The loss of reparative MoMFs was prevented by supplementing CCl 4 -treated ICOS -/- mice with recombinant ICOS (ICOS-Fc) which also stimulated full recovery from liver injury. These data demonstrated that CD8 + T-lymphocytes play a key role in supporting the survival of reparative MoMFs during liver healing trough ICOS/ICOSL-mediated signaling. These observations open the possibility of targeting ICOS/ICOSL dyad as a novel tool for promoting efficient healing following acute liver injury.