CX(3)CR1 TRANSDIFFERENTIATES F4/80 LOW MONOCYTES INTO PRO-INFLAMMATORY F4/80 HIGH MACROPHAGES IN ALCOHOLIC LIVER DISEASE

초록

The expression of chemokine receptor CX3CR1 is related to migration and signaling in cells of themonocyte-macrophage lineage. However, the precise roles of CX3CR1 are unknown in alcoholic liver disease. Here, we showed that mouse F4/80lowCX3CR1low monocytes were transdifferentiated into F4/80highCX3CR1high macrophages with abundant cytoplasm as Kupffer cells. Similarly, human CD16-CX3CR1low monocytes transformed into CD16+CX3CR1high macrophages via co-culturing with HUVECs. In addition, siRNA-induced CX3CL1 suppression of HUVECs attenuated expression of interleukin-1beta(IL-1beta), tumor necrosis factor-alpha(TNF-alpha), and CX3CR1, whereas recombinant CX3CL1 treatment reversed this expression in co-cultured monocytes, suggesting CX3CR1-mediated inflammatory signaling in macrophages. Similarly, hepatic CX3CR1+F4/80high macrophages of CX3CR1+/GFP mice showed higher expression of IL-1beta and TNF-alpha than CX3CR1-F4/80high macrophages of CX3CR1GFP/GFP mice. More interestingly, in alcoholic liver injury, despite similar frequencies of hepatic F4/80high macrophages, CX3CR1GFP/GFP mice showed reduced hepatic fat accumulation, liver injury, and inflammatory responses than CX3CR1+/GFP mice. In conclusion, up-regulation of CX3CR1 expression by endothelial cells contributes to transdifferentiation of F4/80low monocytes into F4/80high macrophages and switch to pro-inflammatory phenotype, subsequently leading to acceleration of alcoholic liver injury. Thus, CX3CR1 could be a novel therapeutic target for pro-inflammatory macrophages in alcoholic liver injury.