C-C motif chemokine ligand 5 confines liver regeneration by down-regulating reparative macrophage-derived hepatocyte growth factor in a forkhead box O 3a-dependent manner.
C-C motif chemokine ligand 5 confines liver regeneration by down-regulating reparative macrophage-derived hepatocyte growth factor in a forkhead box O 3a-dependent manner.
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C-C 基序趋化因子配体 5 通过以叉头盒 O 3a 依赖性方式下调修复性巨噬细胞衍生的肝细胞生长因子来限制肝脏再生。
DOI：
10.1002/hep.32458
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发表时间：
2022-12
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肝再生是肝切除术后肝功能恢复的关键。再生能力有限，加上残肝容量不足，是肝切除术后肝功能衰竭（PHLF）的危险因素。尽管炎症在控制LR中起着重要作用，但其潜在机制仍不清楚。我们发现C‐C基序趋化因子配体（CCL） 5是LR的重要负调节因子。在活体肝移植（LT）的健康供体和PHx小鼠模型中，部分肝切除术（PHx）后CCL5水平升高。Ccl5基因敲除小鼠在90% PHx后存活率提高，70% PHx后36 h LR增强。然而，与野生型（WT）小鼠相比，暴露于生长因子的Ccl5 - / -小鼠的原代肝细胞在体外没有增殖优势。流式细胞术分析显示，70% PHx后，Ccl5 - / -小鼠体内Ly6Clo巨噬细胞比例显著增加。RNA‐测序分析显示，与WT小鼠相比，Ccl5−/−小鼠中分选的巨噬细胞（CD11b+Ly6Clo&hi）的修复基因表达增强。在机制上，CCL5诱导巨噬细胞向促炎Ly6Chi表型转变，从而通过C‐C基序趋化因子受体（CCR） 1 -和CCR5介导的叉头盒O (FoxO) 3a途径抑制肝细胞生长因子（HGF）的产生。最后，阻断CCL5可显著提高小鼠PHx模型的存活率和LR。我们的研究结果表明，抑制CCL5是一种很有希望的策略，可以通过FoxO3a途径增强修复性巨噬细胞的HGF分泌，从而改善再生恢复，这可能会降低PHLF的死亡率。PHx后CCL5以FoxO3a依赖方式下调修复性巨噬细胞来源的HGF示意图。在PHx作用下，肝细胞或非肝细胞CCL5分泌的增加可能通过CCR1 -和CCR5 -介导的FoxO3a信号传导而不是NF - κB抑制修复性巨噬细胞中Hgf的转录。
Liver regeneration (LR) is vital for the recovery of liver function after hepatectomy. Limited regeneration capacity, together with insufficient remnant liver volume, is a risk factor for posthepatectomy liver failure (PHLF) resulting from small‐for‐size syndrome. Although inflammation plays an important role in controlling LR, the underlying mechanisms still remain obscure. We identified C‐C motif chemokine ligand (CCL) 5 as an important negative regulator for LR. CCL5 levels were elevated after partial hepatectomy (PHx), both in healthy donors of living donor liver transplantation (LT) and PHx mouse models. Ccl5 knockout mice displayed improved survival after 90% PHx and enhanced LR 36 h after 70% PHx. However, primary hepatocytes from Ccl5−/− mice exposed to growth factors in vitro showed no proliferation advantage compared to those from wild‐type (WT) mice. Flow cytometry analysis showed that proportions of Ly6Clo macrophages were significantly increased in Ccl5−/− mice after 70% PHx. RNA‐sequencing analysis revealed that sorted macrophages (CD11b+Ly6Clo&hi) manifested enhanced expression of reparative genes in Ccl5−/− mice compared to WT mice. Mechanistically, CCL5 induced macrophages toward proinflammatory Ly6Chi phenotype, thereby inhibiting the production of hepatocyte growth factor (HGF) through the C‐C motif chemokine receptor (CCR) 1– and CCR5‐mediated forkhead box O (FoxO) 3a pathways. Finally, blockade of CCL5 greatly optimized survival and boosted LR in the mouse PHx model. Our findings suggest that inhibition of CCL5 is a promising strategy to improve regeneration restoration by enhancing HGF secretion from reparative macrophages through the FoxO3a pathway, which may potentially reduce the mortality of PHLF. Schematic diagram of CCL5 downregulating reparative macrophage‐derived HGF in a FoxO3a dependent manner after PHx. Increased CCL5 secretion from either hepatocytes or non‐hepatocytes may impede Hgf transcription in reparative macrophages via CCR1‐ and CCR5‐mediated FoxO3a signaling instead of NF‐κB at the proliferation phase when subjected to PHx.
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发表时间：
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期刊：
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影响因子：
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