Abstract
We previously reported that F4/80+ Kupffer cells are subclassified into CD68+ Kupffer cells with phagocytic and ROS producing capacity, and CD11b+ Kupffer cells with cytokine-producing capacity. Carbon tetrachloride (CCl4)-induced hepatic injury is a well-known chemical-induced hepatocyte injury. In the present study, we investigated the immunological role of Kupffer cells/macrophages in CCl4-induced hepatitis in mice. The immunohistochemical analysis of the liver and the flow cytometry of the liver mononuclear cells showed that clodronate liposome (c-lipo) treatment greatly decreased the spindle-shaped F4/80+ or CD68+ cells, while the oval-shaped F4/80+ CD11b+ cells increased. Notably, severe hepatic injury induced by CCl4 was further aggravated by c-lipo-pretreatment. The population of CD11b+ Kupffer cells/macrophages dramatically increased 24 hour (h) after CCl4 administration, especially in c-lipo-pretreated mice. The CD11b+ Kupffer cells expressed intracellular TNF and surface Fas-ligand (FasL). Furthermore, anti-TNF Ab pretreatment (which decreased the FasL expression of CD11b+ Kupffer cells), anti-FasL Ab pretreatment or gld/gld mice attenuated the liver injury induced by CCl4. CD1d−/− mouse and cell depletion experiments showed that NKT cells and NK cells were not involved in the hepatic injury. The adoptive transfer and cytotoxic assay against primary cultured hepatocytes confirmed the role of CD11b+ Kupffer cells in CCl4-induced hepatitis. Interestingly, the serum MCP-1 level rapidly increased and peaked at six h after c-lipo pretreatment, suggesting that the MCP-1 produced by c-lipo-phagocytized CD68+ Kupffer cells may recruit CD11b+ macrophages from the periphery and bone marrow. The CD11b+ Kupffer cells producing TNF and FasL thus play a pivotal role in CCl4-induced acute hepatic injury.
Highlights
Carbon tetrachloride (CCl4) is a highly toxic chemical agent that induces acute hepatic injury, while chronic administration of CCl4 induces fibrosis, cirrhosis and carcinogenesis
CCl4- Induced Hepatic Injury by c-lipo Pretreatment We previously reported that c-lipo or GdCl3 selectively depleted only CD68+ Kupffer cells, but increased the population of CD11b+ Kupffer cells/macrophages, as determined by flow cytometry [18]
The CD11b+ Kupffer cells/macrophages became larger after c-lipo treatment, as indicated by the forward scatter (FS) analysis (Fig. 2, left panels, FS values; 43666.8 vs 40162.9, n = 5, p,0.05), suggesting that they were activated after c-lipo treatment
Summary
Carbon tetrachloride (CCl4) is a highly toxic chemical agent that induces acute hepatic injury, while chronic administration of CCl4 induces fibrosis, cirrhosis and carcinogenesis. These IL-12-producing liver B cells, in contrast to spleen B cells, phagocytose bacteria and kill them [15,16] These liver immune cells, including B cells and their cytokines, primarily act as innate immune effectors against infections and tumors by their T helper-1 immune response in the liver. They sometimes induce hepatic injury, septic shock and multi-organ failure [12,13,17]. We have recently reported that liver F4/80+ Kupffer cells/macrophages can be subclassified almost exclusively into two different subsets; a CD68+ subset with phagocytic, ROS production and bactericidal capacities, and a CD11b+ subset with cytokine (TNF and IL-12) production and antitumor capacities [12,13,18,19]
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