Myeloid-specific targeting of Notch ameliorates murine renal fibrosis via reduced infiltration and activation of bone marrow-derived macrophage.
Myeloid-specific targeting of Notch ameliorates murine renal fibrosis via reduced infiltration and activation of bone marrow-derived macrophage.
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Notch 的骨髓特异性靶向通过减少骨髓源性巨噬细胞的浸润和激活来改善小鼠肾纤维化
DOI：
10.1007/s13238-018-0527-6
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发表时间：
2019-03
期刊：
影响因子：
21.1
通讯作者：
Qin H
中科院分区：
文献类型：
--
作者：
Jiang Y;Wang Y;Ma P;An D;Zhao J;Liang S;Ye Y;Lu Y;Zhang P;Liu X;Han H;Qin H
巨噬细胞在肾脏纤维化中起关键作用。然而，巨噬细胞表现出个体起源和功能的异质性，以及哪一类巨噬细胞参与了肾脏纤维化，其潜在机制尚不清楚。在这项研究中，我们通过破坏转录因子重组信号结合蛋白-Jκ(RBP-J)的基因靶向Notch信号，以揭示其在单侧输尿管梗阻(UUO)诱导的小鼠肾脏纤维化过程中对巨噬细胞的调节作用。髓系特异性阻断RBP-J可减轻肾纤维化，减少细胞外基质沉积和肌成纤维细胞活化，并减弱上皮-间充质转化，这可能是由于转化生长因子-β表达减少所致。同时，RBP-J缺失显著阻碍了纤维化肾脏中巨噬细胞的浸润和激活，尽管其增殖未见改变。通过巨噬细胞清除实验，我们发现肾脏滞留的巨噬细胞的贡献可以忽略不计，但骨髓来源的巨噬细胞在肾脏纤维化中起主要作用。进一步的机制分析表明，Notch阻断通过下调CCR2的表达来减少单核细胞从骨髓中的迁移。最后，我们发现髓系特异性Notch的激活加重了肾纤维化，其机制是通过CCR2+巨噬细胞的浸润来实现的。综上所述，我们的数据揭示了髓系特异性靶向Notch可以通过调节BM来源的巨噬细胞的募集和激活来改善肾脏纤维化，为干预这种疾病提供了一种新的策略。本文的在线版本(10.1007/s13238-0180527-6)包含补充材料，可供授权用户使用。
Macrophages play critical roles in renal fibrosis. However, macrophages exhibit ontogenic and functional heterogeneities, and which population of macrophages contributes to renal fibrosis and the underlying mechanisms remain unclear. In this study, we genetically targeted Notch signaling by disrupting the transcription factor recombination signal binding protein-Jκ (RBP-J), to reveal its role in regulation of macrophages during the unilateral ureteral obstruction (UUO)-induced murine renal fibrosis. Myeloid-specific disruption of RBP-J attenuated renal fibrosis with reduced extracellular matrix deposition and myofibroblast activation, as well as attenuated epithelial-mesenchymal transition, likely owing to the reduced expression of TGF-β. Meanwhile, RBP-J deletion significantly hampered macrophage infiltration and activation in fibrotic kidney, although their proliferation appeared unaltered. By using macrophage clearance experiment, we found that kidney resident macrophages made negligible contribution, but bone marrow (BM)-derived macrophages played a major role in renal fibrogenesis. Further mechanistic analyses showed that Notch blockade reduced monocyte emigration from BM by down-regulating CCR2 expression. Finally, we found that myeloid-specific Notch activation aggravated renal fibrosis, which was mediated by CCR2+ macrophages infiltration. In summary, our data have unveiled that myeloid-specific targeting of Notch could ameliorate renal fibrosis by regulating BM-derived macrophages recruitment and activation, providing a novel strategy for intervention of this disease. The online version of this article (10.1007/s13238-018-0527-6) contains supplementary material, which is available to authorized users.
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