Bone marrow-derived Ly6C(-) macrophages promote ischemia-induced chronic kidney disease
Bone marrow-derived Ly6C(-) macrophages promote ischemia-induced chronic kidney disease
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骨髓来源的 Ly6C(-) 巨噬细胞促进缺血诱发的慢性肾病
DOI：
10.1038/s41419-019-1531-3
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发表时间：
2019
影响因子：
9
通讯作者：
Xu Gang
中科院分区：
文献类型：
--
作者：
Yang Qian;Wang Yuxi;Pei Guangchang;Deng Xuan;Jiang Hongyang;Wu Jianliang;Zhou Cheng;Guo Yi;Yao Ying;Zeng Rui;Xu Gang
巨噬细胞在急性肾损伤（阿基）和随后的慢性肾脏疾病（CKD）后的肾损伤和修复中发挥重要作用。然而，由于巨噬细胞具有高度的可塑性和异质性，因此巨噬细胞亚型在AKI至CKD进展中的功能尚未完全了解。在这里，我们专注于Ly 6C −巨噬细胞，它来自胚胎卵黄囊，发育后驻留在肾脏中。我们发现，C-C趋化因子受体2型（CCR 2）缺陷，这阻止了Ly 6C+巨噬细胞从骨髓迁移到损伤部位，减轻了小鼠缺血诱导的阿基。然而，出乎意料的是，CCR 2缺乏使随后的肾纤维化恶化，其特征是Ly 6C −巨噬细胞的显著肾内浸润。这些Ly 6C −巨噬细胞在野生型（WT）小鼠肾脏缺血再灌注（I/R）后的急性和慢性阶段的数量都更多，我们表明它们是通过骨髓嵌合体来源于骨髓。I/R后，CCR 2 −/−小鼠或WT小鼠中氯膦酸盐脂质体（CL）介导的肾脏Ly 6C −巨噬细胞耗竭减轻了肾损伤和纤维化。相反，从WT小鼠的受损肾脏过继转移Ly 6C −巨噬细胞到免疫缺陷小鼠足以诱导肾损伤和纤维化。来自受损肾脏的Ly 6C −巨噬细胞的转录组测序显示，它们分泌各种细胞因子和生长因子，这些因子与成纤维细胞向肌成纤维细胞的转分化有关。这种转分化效应得到了体外研究的进一步支持，该研究表明Ly 6C −巨噬细胞诱导共培养的成纤维细胞分泌细胞外基质蛋白。总之，缺血后骨髓来源的Ly 6C −巨噬细胞的存在诱导阿基和随后的CKD。
Macrophages play an important role in renal injury and repair after acute kidney injury (AKI) and the subsequent chronic kidney disease (CKD) that often results. However, as macrophages have a high degree of plasticity and heterogeneity, the function(s) of macrophage subtypes in AKI-to-CKD progression are not fully understood. Here, we focused on Ly6C−macrophages, which are derived from the embryonic yolk sac and post-development become resident in the kidneys. We found that C–C chemokine receptor type 2 (CCR2) deficiency, which blocks the migration of Ly6C+macrophages from the bone marrow to the sites of injury, alleviated ischemia-induced AKI in mice. Unexpectedly, though, CCR2 deficiency worsened the subsequent renal fibrosis, which was marked by notable intra-renal infiltration of Ly6C−macrophages. These Ly6C−macrophages were greater in number in both the acute and chronic phases after ischemia reperfusion (I/R) in kidneys of wild type (WT) mice, and we showed them to be derived from the bone marrow by bone marrow chimerism. Clodronate Liposomes (CLs)-mediated depletion of renal Ly6C−macrophages in CCR2−/−mice or in WT mice after I/R alleviated the renal injury and fibrosis. On the contrary, adoptive transfer of Ly6C−macrophages from injured kidneys of WT mice into immune-deficient mice was sufficient to induce renal injury and fibrosis. Transcriptome sequencing of Ly6C−macrophages from injured kidneys revealed that they secreted various cytokines and growth factors, which were associated with the transdifferentiation of fibroblasts into myofibroblasts. This transdifferentiation effect was further supported by in vitro studies showing that Ly6C−macrophages induced the secretion of extracellular matrix proteins from co-cultured fibroblasts. In conclusion, the presence of bone marrow-derived Ly6C−macrophages after ischemia induces AKI and worsens subsequent CKD.