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

Abstract

Although mouse liver F4/80(+) Kupffer cells consist of cytokine-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 (FcγRII), 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, expressed 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 irradiated mice reconstituted liver CD11b(+) cells. Conversely, clodronate pretreatment depleted only liver CD32/CD68(+) cells but not liver CD11b(+) cells and peripheral blood or spleen CD11b(+) monocytes/macrophages. Moreover, the CD32(+) cells might be precursors of CD68(+) cells, as a large proportion of CD32(+) cells expressed the c-kit (CD117), and CD34 and CD32(+) cells acquired CD68 immediately after bacteria administration. CD32/CD68(+) cells, but not CD11b(+) cells, expressed resident macrophage-specific MerTK and CD64 (FcγRI). Challenge with Staphylococcus aureus or liver metastatic EL-4 tumor cells indicated that the CD68(+) subset is engaged in systemic bactericidal activity, whereas the CD11b(+) subset is pivotal for liver antitumor immunity. Human liver CD14(+) Kupffer cells could also be classified into three similar subsets. These results suggest that liver CD68(+) Kupffer cells and CD11b(+) Kupffer cells/macrophages are developmentally and functionally distinct subsets.

In vivo Lipopolysaccharide Tolerance Recruits CD11b⁺ Macrophages to the Liver with Enhanced Bactericidal Activity and Low Tumor Necrosis Factor-Releasing Capability, Resulting in Drastic Resistance to Lethal Septicemia

“…12 a). This result was consistent with previous reports [9,10,18] . Despite the depletion of the CD68 + subset in the liver, LPS-primed mice still showed strong resistance to a lethal bacterial challenge ( Fig.…”

“…The former is also CD11b low , while the latter are CD11b high . Interestingly, Davies et al [22] + subset with strong phagocytic activity (tissue resident) and a CD11b + subset with potent proinflammatory cytokine-producing capability (bone marrow derived) [9,10] . Consistent with the report of Davies et al [22] ( Fig.…”

“…To examine the TNF production by organ mononuclear cells (MNC) in E. coli -challenged mice, MNC were isolated from the liver, spleen, lung, Peyer patches, peripheral blood, and peritoneal exudate, using a Percoll solution-collagenase treatment method as previously described [9][10][11][12][13] . Neutrophils were also isolated from the blood as previously described [14] .…”

“…Phagocytosis of invading bacteria by Kupffer cells is essential for host defense, especially against systemic bacterial infection, because 80% of all macrophages reside in the liver as Kupffer cells and are responsible for the elimination of circulating bacteria from the blood stream. We recently demonstrated that 2 types of F4/80 + Kupffer cells/macrophages exist in the mouse liver [9,10] : one is a CD68 + subset which is considered to be tissue-resident macrophages and demonstrates a potent phagocytic activity, while a CD11b + subset is monocytederived recruited macrophages and has a potent TNFproducing capability. In the present study, using a LPS tolerance mouse model, characterization of those Kupffer cells/macrophages and their roles in systemic E. coli infection were investigated.…”

β‐Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice

“…Detailed flow cytometric and immunohistochemical studies also revealed that the CD68 + cells are large and spindle-shaped, while the CD11b + cells are small and round or oval-shaped (Ikarashi et al, 2013). While large macrophages are more phagocytic and generate increased quantities of lysosomal enzymes, the smaller macrophages release more reactive oxygen species, and appear to be more susceptible to`M1`-type activation and cytokine production.…”