Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization.
Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization.
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DOI：
10.1038/s41419-020-03385-x
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发表时间：
2021-01-21
影响因子：
9
通讯作者：
Xu G
中科院分区：
文献类型：
--
作者：
Zhang Y;Zhang C;Li L;Liang X;Cheng P;Li Q;Chang X;Wang K;Huang S;Li Y;Liu Y;Xu G
炎症在肾纤维化的发生和发展中起着至关重要的作用，最终导致终末期肾病（ESRD）。淋巴管生成在炎症领域有新的关注点。近年来研究发现淋巴管生成与肾纤维化之间存在相关性，但淋巴管内皮细胞（LECs）的来源尚不清楚。据报道，巨噬细胞通过直接和间接机制参与其他组织中的淋巴管生成。我们推测巨噬细胞和淋巴管内皮祖细胞在肾纤维化中有密切的关系。在这项研究中，我们证明了淋巴管生成发生在肾纤维化模型，并与纤维化和巨噬细胞浸润的程度呈正相关。与静息（M0）巨噬细胞和交替活化（M2）巨噬细胞相比，经典活化（M1）巨噬细胞在体内和体外主要转分化为LEC。VEGF-C通过激活VEGFR 3进一步增加M1巨噬细胞极化和转分化为LEC。提示VEGF-C/VEGFR 3通路激活下调巨噬细胞自噬，随后调节巨噬细胞表型。雷帕霉素诱导的巨噬细胞自噬降低了M1巨噬细胞的极化和向LEC的分化。这些结果表明，M1巨噬细胞促进淋巴管生成，并有助于在肾纤维化微环境中形成新的淋巴管，VEGF-C/VEGFR 3信号通过抑制巨噬细胞自噬促进M1极化，然后增加M1巨噬细胞向LEC的转分化。
Inflammation plays a crucial role in the occurrence and development of renal fibrosis, which ultimately results in end-stage renal disease (ESRD). There is new focus on lymphangiogenesis in the field of inflammation. Recent studies have revealed the association between lymphangiogenesis and renal fibrosis, but the source of lymphatic endothelial cells (LECs) is not clear. It has also been reported that macrophages are involved in lymphangiogenesis through direct and indirect mechanisms in other tissues. We hypothesized that there was a close relationship between macrophages and lymphatic endothelial progenitor cells in renal fibrosis. In this study, we demonstrated that lymphangiogenesis occurred in a renal fibrosis model and was positively correlated with the degree of fibrosis and macrophage infiltration. Compared to resting (M0) macrophages and alternatively activated (M2) macrophages, classically activated (M1) macrophages predominantly transdifferentiated into LECs in vivo and in vitro. VEGF-C further increased M1 macrophage polarization and transdifferentiation into LECs by activating VEGFR3. It was suggested that VEGF-C/VEGFR3 pathway activation downregulated macrophage autophagy and subsequently regulated macrophage phenotype. The induction of autophagy in macrophages by rapamycin decreased M1 macrophage polarization and differentiation into LECs. These results suggested that M1 macrophages promoted lymphangiogenesis and contributed to newly formed lymphatic vessels in the renal fibrosis microenvironment, and VEGF-C/VEGFR3 signaling promoted macrophage M1 polarization by suppressing macrophage autophagy and then increased the transdifferentiation of M1 macrophages into LECs.
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影响因子：
3.7
作者：
Jiang S;Bailey AS;Goldman DC;Swain JR;Wong MH;Streeter PR;Fleming WH
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