Background & aims

Macrophages are key regulators of inflammation and cancer promotion in the liver, and their recruitment and activation is linked to chemokine receptor signaling. However, the exact roles of the chemokine receptors CCR2 and CCR5 for macrophage functions in the liver is obscure.

Methods

To study CCR2 and CCR5 in inflammatory liver injury, we used mice with a hepatocyte-specific knock-out of the nuclear factor κB (NF-κB) essential modulator (NEMO), termed NEMO^LPC-KO mice, and generated NEMO^LPC-KOCcr2^-/- and NEMO^LPC-KOCcr5^-/- mice. NEMO^LPC-KO mice develop hepatitis and fibrosis after two and liver tumors after six months.

Results

We found that both CCR2 and CCR5 deficiency led to reduced fibrosis, while CCR5 deficiency increased steatosis and tumor burden in NEMO^LPC-KO mice. CCR2 was required for recruitment of hepatic macrophages, whereas CCR5 promoted stellate cell activation. The reduction of monocytes and macrophages by either anti-Gr1 antibody or clodronate-loaded liposomes (CLL), but not of CD8⁺ T cells or NK cells, significantly aggravated liver injury in NEMO^LPC-KO mice and was further increased in NEMO^LPC-KOCcr5^-/- mice. CLL-induced liver injury was dampened by the adoptive transfer of ex vivo generated macrophages, whereas the adoptive transfer of control CD115⁺ immature monocytes or B cells did not reduce liver injury.

Conclusions

Although CCR2 and CCR5 principally promote liver fibrosis, they exert differential functions on hepatic macrophages during liver disease progression in NEMO^LPC-KO mice. While CCR2 controls the recruitment of monocytes to injured livers, CCR5-dependent functions of liver macrophages limit hepatic injury, thereby reducing steatosis and hepatocarcinogenesis.

中文翻译：

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CCR2 和 CCR5 对肝实质细胞特异性 NEMO 缺失小鼠肝巨噬细胞极化的作用。

背景与目标

巨噬细胞是肝脏炎症和癌症促进的关键调节剂，它们的募集和激活与趋化因子受体信号传导有关。然而，趋化因子受体 CCR2 和 CCR5 对肝脏巨噬细胞功能的确切作用尚不清楚。

方法

为了研究炎症性肝损伤中的 CCR2 和 CCR5，我们使用了肝细胞特异性敲除核因子 κB (NF-κB) 必需调节剂 (NEMO) 的小鼠，称为 NEMO ^LPC-KO小鼠，并生成了 NEMO ^LPC-KO Ccr2 ^-/-和 NEMO ^LPC-KO Ccr5 ^-/-小鼠。NEMO ^LPC-KO小鼠在两个月后出现肝炎和纤维化，六个月后出现肝脏肿瘤。

结果

我们发现 CCR2 和 CCR5 缺乏导致纤维化减少，而 CCR5 缺乏增加了 NEMO ^LPC-KO小鼠的脂肪变性和肿瘤负荷。CCR2 是募集肝巨噬细胞所必需的，而 CCR5 促进星状细胞活化。抗 Gr1 抗体或负载氯膦酸盐的脂质体 (CLL) 减少单核细胞和巨噬细胞，但不减少 CD8 ⁺ T 细胞或 NK 细胞，显着加重了 NEMO ^LPC-KO小鼠的肝损伤，并在 NEMO ^{LPC- KO} Ccr5 ^-/-小鼠。体外产生的巨噬细胞的过继转移抑制了 CLL 诱导的肝损伤，而对照 CD115 ⁺ 未成熟的单核细胞或 B 细胞并没有减少肝损伤。

结论

尽管 CCR2 和 CCR5 主要促进肝纤维化，但它们在 NEMO ^LPC-KO小鼠的肝病进展过程中对肝巨噬细胞发挥不同的功能。虽然 CCR2 控制单核细胞向受损肝脏的募集，但肝脏巨噬细胞的 CCR5 依赖性功能限制了肝脏损伤，从而减少了脂肪变性和肝癌发生。