Distinct development and functions of resident and recruited liver Kupffer cells/macrophages

Although mouse liver F4/80 Kupffer cells consist of cy-tokine-producing CD11b cells and phagocytic CD68 cells, an undefined CD11b CD68 subset (30%) also exists. We herein demonstrate a more fundamental classification by adding CD32 (FcRII), which covers most liver F4/80 cells and the distinct functions of them. Among the F4/80 cells, 50%, 40%, and 30 % of cells were CD32, CD68, and CD11b, respectively, and one-half of the CD68 cells coexpressed CD32. CD68 and CD32 cells, but not CD11b cells, ex-pressed a phagocytosis-related CRIg. Gy (6) irradiation depleted liver CD11b cells and those in the spleen, bone marrow, and peripheral blood but not liver CD32/ CD68 cells. Transfer of bone marrow cells into the ir-radiated mice reconstituted liver CD11b cells. Con-versely, clodronate pretreatment depleted only liver CD32/CD68 cells but not liver CD11b cells and periph-eral blood or spleen CD11b monocytes/macrophages. Moreover, the CD32 cells might be precursors of CD68 cells, as a large proportion of CD32 cells ex-pressed the c-kit (CD117), and CD34 and CD32 cells acquired CD68 immediately after bacteria administra-tion. CD32/CD68 cells, but not CD11b cells, ex-pressed resident macrophage-specific MerTK and CD64 (FcRI). Challenge with Staphylococcus aureus or liver metastatic EL-4 tumor cells indicated that the CD68 subset is engaged in systemic bactericidal ac-tivity, whereas the CD11b subset is pivotal for liver an-titumor immunity. Human liver CD14 Kupffer cells could also be classified into three similar subsets. These re-sults suggest that liver CD68 Kupffer cells and CD11b Kupffer cells/macrophages are developmentally and functionally distinct subsets. J. Leukoc. Biol. 94: 1325–1336; 2013