Changes in Function and Dynamics in Hepatic and Splenic Macrophages in Non-Alcoholic Fatty Liver Disease

Background: The aim of this study was to investigate the populations and functions of hepatic and splenic macrophages (Mfs) in non-alcoholic fatty liver disease (NAFLD). Materials and Methods: Experiment 1: Wild-type and STAM (R) mice were given chow or high-fat diets for designated periods. In isolated Mfs, phagocytosis and cytokine production were assessed. Immunohistochemistry for CD68 and F4/80 and expression of CD14 and CD16 were assessed. Experiment 2: Bone marrow cells harvested from enhanced green fluorescent protein (EGFP) mice were transplanted into wild-type mice with or without splenectomy after total body irradiation that was kept on methionine- and choline-deficient diets. Results: Experiment 1: The number of CD68-positive cells and the percentage of F4/80-positive/CD68-positive cells increased with the progression of NAFLD. Production of TNF-alpha and IL-6 by hepatic Mfs was greater than that by splenic Mfs in mice with NASH. The number of CD14(+)CD16(-) Mfs increased in the spleen and decreased in the liver in animals that had progressed to NASH. Furthermore, the number of CD14(+)CD16(+) hepatic Mfs was increased in animals that had progressed to NASH with fibrosis. Experiment 2: EGFP-positive cells were observed in the liver after transplantation. In the splenectomy group, EGFP-positive Mfs were also observed; however, the number was significantly less than that in the sham operation group. Conclusion: The populations and functions of hepatic and splenic Mfs are altered during the progression of NAFLD. In addition, increased hepatic Mfs during the progression of NAFLD may migrate from bone marrow to the liver via the spleen.