Distinct Macrophage Phenotypes Contribute to Kidney Injury and Repair
Distinct Macrophage Phenotypes Contribute to Kidney Injury and Repair
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DOI：
10.1681/asn.2009060615
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发表时间：
2011-02-01
影响因子：
13.6
通讯作者：
Cantley, Lloyd G.
中科院分区：
文献类型：
--
作者：
Lee, Sik;Huen, Sarah;Cantley, Lloyd G.
缺血损伤的肾脏发生肾小管细胞坏死和凋亡，并伴有间质炎性细胞浸润。在这项研究中，我们发现iNos阳性的促炎性（M1）巨噬细胞在缺血/再灌注损伤后的前48小时内被招募到肾脏中，而在随后的时间点，脱氢酶1和甘露糖受体阳性的非炎性（M2）巨噬细胞占主导地位。此外，缺血/再灌注前巨噬细胞的消耗减少了肾损伤，而损伤后3至5天的消耗减缓了肾小管细胞的增殖和修复。在肾脏再灌注时，将IFN γ刺激的骨髓源性巨噬细胞输注到巨噬细胞耗竭的小鼠中，将损伤恢复到未出现巨噬细胞耗竭的水平，表明促炎性巨噬细胞加重了肾脏损伤。相反，M2表型巨噬细胞的出现与肾修复的增殖期相关。体外研究表明，IFN-γ刺激的促炎性巨噬细胞在与肾小管细胞共培养时开始表达M2巨噬细胞的标志物。此外，IL-4刺激具有M2表型的巨噬细胞，而不是IFN γ刺激的促炎性巨噬细胞，促进肾小管细胞增殖。最后，追踪荧光标记的，IFN γ刺激的巨噬细胞在损伤后注射，表明炎症巨噬细胞可以在肾脏修复开始时转换为M2表型。总之，这些研究表明，巨噬细胞经历了从促炎表型到营养表型的转变，支持从小管损伤到小管修复的转变。
The ischemically injured kidney undergoes tubular cell necrosis and apoptosis, accompanied by an interstitial inflammatory cell infiltrate. In this study, we show that iNos-positive proinflammatory (M1) macrophages are recruited into the kidney in the first 48 hours after ischemia/reperfusion injury, whereas arginase 1- and mannose receptor positive, noninflammatory (M2) macrophages predominate at later time points. Furthermore, depletion of macrophages before ischemia/reperfusion diminishes kidney injury, whereas depletion at 3 to 5 days after injury slows tubular cell proliferation and repair. Infusion of Ifn gamma-stimulated, bone marrow-derived macrophages into macrophage-depleted mice at the time of kidney reperfusion restored injury to the level seen without macrophage depletion, suggesting that proinflammatory macrophages worsen kidney damage. In contrast, the appearance of macrophages with the M2 phenotype correlated with the proliferative phase of kidney repair. In vitro studies showed that IFN-gamma-stimulated, proinflammatory macrophages begin to express markers of M2 macrophages when cocultured with renal tubular cells. Moreover, IL-4 stimulated macrophages with an M2 phenotype, but not IFN gamma-stimulated proinflammatory macrophages, promoted renal tubular cell proliferation. Finally, tracking fluorescently labeled, IFN gamma-stimulated macrophages that were injected after injury showed that inflammatory macrophages can switch to an M2 phenotype in the kidney at the onset of kidney repair. Taken together, these studies show that macrophages undergo a switch from a proinflammatory to a trophic phenotype that supports the transition from tubule injury to tubule repair.