Roles of CD68 in macrophage function, host defense, atherosclerosis and autoimmunity

Murine CD68 (macrosialin) is a plasma membrane protein expressed in macrophages and macrophage-related cells, including langerhans cells, dendritic cells, and osteoclasts. Although the function of CD68 is unknown, it has been postulated to play roles in phagocytosis and cell-pathogen interactions as it is strongly expressed in monocytes and undergoes changes in expression during inflammatory responses. Some studies suggested that CD68 is capable of binding a wide range of ligands, including bacteria pathogens, oxidatively modified low-density lipoprotein (OxLDL), and oxidatively damaged cells. It has also been proposed that it may be involved in antigen presentation. Although CD68 is localized predominantly intracellularly in late endosomes, it exhibits rapid translocation between intracellular membranes and the plasma membrane. Relatively low levels of surface CD68 expression may thus be sufficient for the rapid uptake of various ligands by macrophages. In this study, we generated CD68-deficient mice by gene targeting. The CD68-deficient animals were more susceptible to bacterial infection than the wild type littermates, and macrophages from CD68-deficient mice were defective in bacterial binding and phagocytosis both in vivo and in vitro. In addition, the macrophage binding of oxidatively damaged red blood cell (OxRBC) was dramatically reduced in CD68-deficient mice. These results indicate that CD68 plays a protective role in host defense and that it may function in apoptosis by clearing oxidatively damaged cells. More surprisingly, CD68-deficient mice exhibited evidence of autoimmune diabetes, including pancreatic inflammation, reduced insulin production, and elevated plasma glucose. The CD68-deficient mice also exhibited increased atherosclerosis, elevated levels of auto-antibodies against chromatin and double strand DNA, and infiltration of lymphocytes in multiple tissues such as kidney, lung, and adipose tissue, indicating the development of a murine lupus alike disorder. The CD68 deficient mouse thus provides an excellent model for the investigation of antigen presenting cell (APC) dysfunction and their roles in the development of diseases.