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 CX₃CR1^lowF4/80^low monocytes and CX₃CR1^lowCD16^- monocytes were differentiated into CX₃CR1^highF4/80^high or CX₃CR1^highCD16⁺ 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 F4/80^high macrophages were successfully depleted at day 2 and recovered similarly in CX₃CR1^+/GFP and CX₃CR1^GFP/GFP mice at week 4, suggesting a CX₃CR1-independent replacement. However, F4/80^high macrophages of CX₃CR1^+/GFP showed a stronger pro-inflammatory phenotype than CX₃CR1^GFP/GFP mice. In clodronate-treated chimeric CX₃CR1^+/GFP and CX₃CR1^GFP/GFP mice, CX₃CR1⁺F4/80^high macrophages showed higher expression of IL-1β and TNF-α than CX₃CR1^-F4/80^high macrophages. In alcoholic liver injury, despite the similar frequency of hepatic F4/80^high macrophages, CX₃CR1^GFP/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.

中文翻译：

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CX3CR1在肝脏中将F4 / 80低单核细胞分化为促炎性F4 / 80高巨噬细胞。

趋化因子受体CX ₃ CR1的表达与单核巨噬细胞谱系细胞中的迁移和信号传导有关。已经研究了CX ₃ CR1在肝脏中的确切作用，但尚未明确阐明。在这里，我们调查了CX ₃ CR1在肝巨噬细胞和肝损伤中的作用。肝和脾CX ₃ CR1^低F4 / 80^低的单核细胞和CX ₃ CR1^低CD16 ^-单核细胞分化为CX ₃ CR1^高F4 / 80^高或CX ₃ CR1^高CD16 ⁺巨噬细胞与内皮细胞共培养。此外，人脐静脉内皮细胞（HUVECs）中CX ₃ CL1的缺乏减弱了白介素1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的表达，而重组CX ₃ CL1处理逆转了这种表达。培养的单核细胞。用氯膦酸盐脂质体处理后，肝F4 / 80^高巨噬细胞在第2天成功耗尽，并在第4周在CX ₃ CR1 ^{+ / GFP}和CX ₃ CR1 ^{GFP / GFP}小鼠中类似地恢复，表明是CX ₃ CR1独立的替代。但是，CX ₃ CR1的F4 / 80^高巨噬细胞^{+ / GFP}显示出比CX ₃ CR1 ^{GFP / GFP}小鼠更强的促炎表型。在用氯膦酸盐处理过的嵌合CX ₃ CR1 ^{+ / GFP}和CX ₃ CR1 ^{GFP / GFP}小鼠中，CX ₃ CR1 ⁺ F4 / 80^高巨噬细胞的IL-1β和TNF-α表达高于CX ₃ CR1 ^- F4 / 80^高巨噬细胞。在酒精性肝损伤中，尽管肝F4 / 80^高巨噬细胞的发生频率相似，但CX ₃ CR1 ^{GFP / GFP}小鼠显示出比CX ₃ CR1 ^{+ / GFP}小鼠减少的肝损伤，肝脂肪蓄积和炎症反应。因此，CX ₃ CR1可能是促炎性巨噬细胞介导的肝损伤的新型治疗靶点。