Myeloid-Specific Disruption of Recombination Signal Binding Protein Jκ Ameliorates Hepatic Fibrosis by Attenuating Inflammation Through Cylindromatosis in Mice
Myeloid-Specific Disruption of Recombination Signal Binding Protein Jκ Ameliorates Hepatic Fibrosis by Attenuating Inflammation Through Cylindromatosis in Mice
复制标题
重组信号结合蛋白 J kappa 的骨髓特异性破坏通过减轻小鼠圆柱瘤病的炎症来改善肝纤维化
DOI：
10.1002/hep.27394
复制
发表时间：
2015-01-01
期刊：
影响因子：
13.5
通讯作者：
Han, Hua
中科院分区：
文献类型：
--
作者：
He, Fei;Guo, Feng-Cheng;Han, Hua
巨噬细胞在肝纤维化中发挥多维作用，但其调控机制尚不完全清楚。由4种哺乳动物Notch受体信号反式激活的转录因子重组信号结合蛋白J(RBP-J)介导的Notch途径与巨噬细胞的激活和可塑性有关。在这项研究中，通过使用小鼠肝纤维化模型，我们证明了髓系特异性的RBP-J破坏导致了减轻的纤维化。髓系特异性RBP-J缺陷小鼠肝星状细胞的活化和促纤维化因子包括血小板衍生生长因子(PDGF)-B和转化生长因子-β1(TGF-1)的产生明显减少。髓系特异性RBP-J缺陷小鼠在肝纤维化过程中，肝组织炎性细胞的浸润减少，促炎症因子的产生减少。在RBP-J缺陷的巨噬细胞中，核因子-kappaB(NF-B)的激活与对照组相比明显减弱。这可能是由于在Notch信号受损的巨噬细胞中上调了核因子-B的负性调节因子--圆柱瘤病(CyLD)，因为在RBP-J缺陷的巨噬细胞中CyLD的下调或在RBP-J敲除细胞中p65的过表达都恢复了巨噬细胞的NF-B激活和促炎和/或促纤维化因子的产生。在人的肝纤维化活检中，较强的Notch激活与更严重的纤维化相关，这伴随着较低的CyLD水平，但与病因无关。结论：RBP-J介导的Notch信号是巨噬细胞通过CyLD上调核因子-B活化促进肝纤维化所必需的。(《肝病》2015；61：303-314)
Macrophages play multidimensional roles in hepatic fibrosis, but their control has not been fully understood. The Notch pathway mediated by recombination signal binding protein J (RBP-J), the transcription factor transactivated by signals from four mammalian Notch receptors, is implicated in macrophage activation and plasticity. In this study, by using mouse hepatic fibrosis models, we show that myeloid-specific disruption of RBP-J resulted in attenuated fibrosis. The activation of hepatic stellate cells and production of profibrotic factors including platelet-derived growth factor (PDGF)-B and transforming growth factor beta1 (TGF-1) reduced significantly in myeloid-specific RBP-J deficient mice. The infiltration of inflammatory cells and production of proinflammatory factors were reduced in liver of myeloid-specific RBP-J-deficient mice during fibrosis. In RBP-J-deficient macrophages, the nuclear factor kappa B (NF-B) activation was remarkably attenuated as compared with the control. This could be attributed to the up-regulation of cylindromatosis (CYLD), a negative regulator of NF-B, in Notch signal-compromised macrophages, because the knockdown of CYLD in RBP-J-deficient macrophages or overexpression of p65 in RBP-J knockdown cells both restored NF-B activation and the production of proinflammatory and/or profibrotic factors by macrophages. In human hepatic fibrosis biopsies, stronger Notch activation is correlated with more severe fibrosis, which is accompanied by a lower level of CYLD but irrespective of etiological reasons. Conclusion: RBP-J-mediated Notch signaling is required for macrophages to promote hepatic fibrosis by up-regulation of NF-B activation through CYLD. (Hepatology 2015;61:303-314)