The Emerging Role of T Cell Immunoglobulin Mucin-1 in the Mechanism of Liver Ischemia and Reperfusion Injury in the Mouse

The T cell immunoglobulin and mucin domain-containing molecules (TIM) protein family, which is expressed by T cells, plays a crucial role in regulating host adaptive immunity and tolerance. However, its role in local inflammation, such as innate immunity-dominated organ ischemia-reperfusion injury (IRI), remains unknown. Liver IRI occurs frequently after major hepatic resection or liver transplantation. Using an antagonistic anti-TIM-1 antibody (Ab), we studied the role of TIM-1 signaling in the model of partial warm liver ischemia followed by reperfusion. Anti-TIM-1 Ab monotherapy ameliorated the hepatocellular damage and improved liver function due to IR, as compared with controls. Histological examination has revealed that anti-TIM-1 Ab treatment decreased local neutrophil infiltration, inhibited sequestration of T lymphocytes, macrophages, TIM-1 ligand-expressing TIM-4(+) cells, and reduced liver cell apoptosis. Intrahepatic neutrophil activity and induction of proinflammatory cytokines/ chemokines were also reduced in the treatment group. In parallel in vitro studies, anti TIM-1 Ab suppressed interferon-gamma (IFN-gamma) production in concanavalin A (conA)-stimulated spleen T cells, and diminished tumor necrosis factor a (TNF-alpha)/interleukin (IL)-6 expression in a macrophage/spleen T cell coculture system. This is the first study to provide evidence for the novel role of TIM-1 signaling in the mechanism of liver IRI. TIM-1 regulates not only T for the role of cell activation but may also affect macrophage function in the local inflammation response. These results provide compelling data for further investigation of TIM-1 pathway in the mechanism of IRI, to improve liver function, expand the organ donor pool, and improve the overall success of liver transplantation. (HFPATOLOGY 2010;51:1363-1372.)