Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis.
Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis.
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DOI：
10.1371/journal.pone.0011049
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发表时间：
2010-06-10
期刊：
影响因子：
3.7
通讯作者：
Tacke F
中科院分区：
文献类型：
--
作者：
Zimmermann HW;Seidler S;Nattermann J;Gassler N;Hellerbrand C;Zernecke A;Tischendorf JJ;Luedde T;Weiskirchen R;Trautwein C;Tacke F
单核细胞衍生的巨噬细胞在肝损伤后作为器官纤维化的先决条件严重地延续炎症反应。实验小鼠模型确定了经典Gr 1/Ly 6C+单核细胞的CCR 2依赖性浸润在肝纤维化中的重要作用。此外，单核细胞相关趋化因子受体CCR 1和CCR 5最近被认为是小鼠中重要的纤维化调节剂。在人类中，单核细胞由经典CD 14 + CD 16 −和非经典CD 14 + CD 16+细胞组成。我们旨在研究单核细胞亚群与人类肝纤维化的相关性，并假设在肝病进展过程中，“非经典”单核细胞在患者中严重发挥炎症和促纤维化功能。我们通过流式细胞术分析了226例慢性肝病（CLD）患者和184例健康对照者新鲜抽取的血液样本中的循环单核细胞亚群。与对照组相比，CLD患者的循环单核细胞显著扩增，非经典CD 14 + CD 16+亚群显著增加，显示患者的活化表型，并与促炎细胞因子和临床进展相关。相应地，CD 14 + CD 16+巨噬细胞大量积聚在纤维化/硬化肝脏中，如免疫荧光和FACS所证明的。单核细胞相关趋化因子受体CCR 2、CCR 1和CCR 5的配体在纤维化和硬化肝脏中表达水平较高，而CCL 3和CCL 4在CLD患者中也全身性升高。分离的单核细胞/巨噬细胞亚群的功能特征有关细胞因子/趋化因子的表达和相互作用与原代人肝星状细胞（HSC）在体外。CD 14 + CD 16+单核细胞释放大量促炎细胞因子。此外，CD 14 + CD 16+单核细胞（而非CD 14 + CD 16 −单核细胞）可直接激活产生胶原的HSC。我们的数据表明，CD 14 + CD 16+单核细胞在疾病进展后的循环和肝脏的CLD患者的扩张，并建议他们的功能性贡献的肝内炎症和肝硬化促纤维化HSC激活的永久化。通过趋化因子/趋化因子受体调节单核细胞亚群向肝脏的募集及其随后的分化可能代表了人类肝纤维化治疗干预的有前景的方法。
Monocyte-derived macrophages critically perpetuate inflammatory responses after liver injury as a prerequisite for organ fibrosis. Experimental murine models identified an essential role for the CCR2-dependent infiltration of classical Gr1/Ly6C+ monocytes in hepatic fibrosis. Moreover, the monocyte-related chemokine receptors CCR1 and CCR5 were recently recognized as important fibrosis modulators in mice. In humans, monocytes consist of classical CD14+CD16− and non-classical CD14+CD16+ cells. We aimed at investigating the relevance of monocyte subpopulations for human liver fibrosis, and hypothesized that ‘non-classical’ monocytes critically exert inflammatory as well as profibrogenic functions in patients during liver disease progression. We analyzed circulating monocyte subsets from freshly drawn blood samples of 226 patients with chronic liver disease (CLD) and 184 healthy controls by FACS analysis. Circulating monocytes were significantly expanded in CLD-patients compared to controls with a marked increase of the non-classical CD14+CD16+ subset that showed an activated phenotype in patients and correlated with proinflammatory cytokines and clinical progression. Correspondingly, CD14+CD16+ macrophages massively accumulated in fibrotic/cirrhotic livers, as evidenced by immunofluorescence and FACS. Ligands of monocyte-related chemokine receptors CCR2, CCR1 and CCR5 were expressed at higher levels in fibrotic and cirrhotic livers, while CCL3 and CCL4 were also systemically elevated in CLD-patients. Isolated monocyte/macrophage subpopulations were functionally characterized regarding cytokine/chemokine expression and interactions with primary human hepatic stellate cells (HSC) in vitro. CD14+CD16+ monocytes released abundant proinflammatory cytokines. Furthermore, CD14+CD16+, but not CD14+CD16− monocytes could directly activate collagen-producing HSC. Our data demonstrate the expansion of CD14+CD16+ monocytes in the circulation and liver of CLD-patients upon disease progression and suggest their functional contribution to the perpetuation of intrahepatic inflammation and profibrogenic HSC activation in liver cirrhosis. The modulation of monocyte-subset recruitment into the liver via chemokines/chemokine receptors and their subsequent differentiation may represent promising approaches for therapeutic interventions in human liver fibrosis.
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影响因子：
29.4
作者：
Imamura, M;Ogawa, T;Ueno, H
通讯作者：
Ueno, H
影响因子：
32.4
作者：
Serbina, NV;Salazar-Mather, TP;Pamer, EG
通讯作者：
Pamer, EG
影响因子：
15.1
作者：
Koch, Alexander;Gressner, Olav A.;Trautwein, Christian
通讯作者：
Trautwein, Christian
影响因子：
13.5
作者：
DESMET, VJ;GERBER, M;SCHEUER, PJ
通讯作者：
SCHEUER, PJ
影响因子：
15.9
作者：
Duffield, JS;Forbes, SJ;Iredale, JP
通讯作者：
Iredale, JP