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Sci Rep. 2018 Oct 10;8(1):15076. doi: 10.1038/s41598-018-33440-9.

CX3CR1 differentiates F4/80low monocytes into pro-inflammatory F4/80high macrophages in the liver.

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Department of Internal Medicine, Korea University College of Medicine, Seoul, 08308, Republic of Korea.
Lab of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141, Republic of Korea.
Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 34952, Republic of Korea.
Department of Oral Medicine, School of Dentistry, Kyungpook National University, Daegu, 41940, Republic of Korea.
Lab of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141, Republic of Korea.


The expression of chemokine receptor CX3CR1 is related to migration and signaling in cells of the monocyte-macrophage lineage. The precise roles of CX3CR1 in the liver have been investigated but not clearly elucidated. Here, we investigated the roles of CX3CR1 in hepatic macrophages and liver injury. Hepatic and splenic CX3CR1lowF4/80low monocytes and CX3CR1lowCD16- monocytes were differentiated into CX3CR1highF4/80high or CX3CR1highCD16+ macrophages by co-culture with endothelial cells. Moreover, CX3CL1 deficiency in human umbilical vein endothelial cells (HUVECs) attenuated the expression of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), whereas recombinant CX3CL1 treatment reversed this expression in co-cultured monocytes. Upon treatment with clodronate liposome, hepatic F4/80high macrophages were successfully depleted at day 2 and recovered similarly in CX3CR1+/GFP and CX3CR1GFP/GFP mice at week 4, suggesting a CX3CR1-independent replacement. However, F4/80high macrophages of CX3CR1+/GFP showed a stronger pro-inflammatory phenotype than CX3CR1GFP/GFP mice. In clodronate-treated chimeric CX3CR1+/GFP and CX3CR1GFP/GFP mice, CX3CR1+F4/80high macrophages showed higher expression of IL-1β and TNF-α than CX3CR1-F4/80high macrophages. In alcoholic liver injury, despite the similar frequency of hepatic F4/80high macrophages, CX3CR1GFP/GFP mice showed reduced liver injury, hepatic fat accumulation, and inflammatory responses than CX3CR1+/GFP mice. Thus, CX3CR1 could be a novel therapeutic target for pro-inflammatory macrophage-mediated liver injury.

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