Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow-Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice.
Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow-Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice.
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DOI：
10.4049/jimmunol.1601565
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发表时间：
2017-04-01
期刊：
影响因子：
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通讯作者：
Lawler JR
中科院分区：
文献类型：
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作者：
Sung SJ;Ge Y;Dai C;Wang H;Fu SM;Sharma R;Hahn YS;Yu J;Le TH;Okusa MD;Bolton WK;Lawler JR
由肾小球浸润性骨髓源性细胞介导的肾小球损伤是狼疮性肾炎 (LN)c 的关键致病事件，但对该过程知之甚少。对肾脏切片进行共聚焦显微镜检查，并对磁珠纯化肾小球中的肾小球细胞进行流式细胞术分析，在患有自发性慢性肾小球肾炎 (cGN) 和抗肾小球基底膜 (GBM) 诱导的 NZM2328 (NZM) 狼疮易感小鼠中鉴定出肾小球浸润白细胞群 肾炎。主要肾小球浸润性 CD11b+F4/80−I-A− 巨噬细胞群的出现，表现出 PD-L1、Mac-2 和巨噬细胞甘露糖受体 (MMR、CD206) 标记，并产生 Klf4、Il10、Retnla、Tnf 和 Il6 mRNA，已知这些 mRNA 是由替代激活 (M2b) 巨噬细胞表达的 蛋白尿状态。在患有自发性 LN 的 NZM 小鼠中，肾小球巨噬细胞浸润占主导地位。 CD11b+F4/80−I-A− 肾小球内巨噬细胞和 PMN 在诱导 GN 中很重要，因为抗 CD11b 和 ICAM-1 mAb 抑制蛋白尿以及巨噬细胞和 PMN 浸润。 GN 小鼠肾脏中 CD11b+F4/80−I-A− 肾小球巨噬细胞对 PD-L1 的显着高表达以及抗 PD-L1 mAb 对蛋白尿的抑制支持了这些巨噬细胞而非 PD-L1− PMN 在 GN 发展和诱导足细胞损伤中的致病作用。在患有自发性 cGN 和严重蛋白尿的 NZM 小鼠中，发现很少的肾小球浸润性 PMN，留下巨噬细胞和较小程度的 DC 作为主要浸润性白细胞。这些数据共同支持 CD11b+F4/80−I-A− M2b 样肾小球浸润巨噬细胞在 LN 中的重要致病作用，并强化巨噬细胞作为 GN 治疗的有希望的靶点。
Glomerular damage mediated by glomerulus-infiltrating myeloid-derived cells is a key pathogenic event in lupus nephritis (LN)c but the process is poorly understood. Confocal microscopy of kidney sections and flow cytometry analysis of glomerular cells from magnetic-bead purified glomeruli have identified glomerulus-infiltrating leukocyte populations in NZM2328 (NZM) lupus-prone mice with spontaneous chronic glomerulonephritis (cGN) and anti-glomerular basement membrane (GBM)-induced nephritis. The occurrence of a major glomerulus-infiltrating CD11b+F4/80−I-A− macrophage population exhibiting the markers PD-L1, Mac-2, and macrophage mannose receptor (MMR, CD206) and producing Klf4, Il10, Retnla, Tnf, and Il6 mRNA which are known to be expressed by alternatively activated (M2b) macrophages correlated with proteinuria status. In NZM mice with spontaneous LN, glomerular macrophage infiltration is predominant. CD11b+F4/80−I-A− intraglomerular macrophages and PMN are important in inducing GN as anti- CD11b and ICAM-1 mAb inhibited both proteinuria and macrophage and PMN infiltration. The predominant and high expression of PD-L1 by CD11b+F4/80−I-A− glomerular macrophages in kidneys of mice with GN and the inhibition of proteinuria by anti-PD-L1 mAb supported the pathogenic role of these macrophages but not the PD-L1− PMN in GN development and in inducing podocyte damage. In NZM mice with spontaneous cGN and severe proteinuria, few glomerulus-infiltrating PMN were found, leaving macrophages and to a lesser extent DC as the major infiltrating leukocytes. These data taken together support the important pathogenic effect of CD11b+F4/80−I-A− M2b-like glomerulus-infiltrating macrophages in LN and reinforce macrophages as a promising target for GN treatment.