The calcium-binding protein complex S100A8/A9 has a crucial role in controlling macrophage-mediated renal repair following ischemia/reperfusion
The calcium-binding protein complex S100A8/A9 has a crucial role in controlling macrophage-mediated renal repair following ischemia/reperfusion
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DOI：
10.1038/ki.2014.216
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发表时间：
2015-01-01
影响因子：
19.6
通讯作者：
Leemans, Jaklien C.
中科院分区：
文献类型：
--
作者：
Dessing, Mark C.;Tammaro, Alessandra;Leemans, Jaklien C.
在缺血/再灌注（I/R）诱导的损伤后，几种损伤相关的分子模式表达，包括钙结合蛋白S100 A8/A9复合物。S100 A8/A9可以被Toll样受体4识别，并且已知其活化有害地促进肾I/R诱导的损伤。为了进一步测试这一点，对野生型和S100 A9敲除小鼠（S100 A8/A9复合物缺陷）进行肾I/R。S100 A8/A9的表达在I/R后1天显著增加，并且与Ly 6 G（小鼠中性粒细胞标志物）阳性细胞共定位。这些敲除小鼠在此早期时间点与野生型小鼠相比显示出相似的肾功能障碍和损伤以及中性粒细胞内流。有趣的是，S100 A9敲除小鼠在I/R后5天和10天显示出改变的组织修复，如通过增加的肾损伤、持续的炎症、纤维化诱导和胶原蛋白表达增加所反映的。这与交替活化的巨噬细胞（M2）标志物的表达增强相一致，而经典活化的巨噬细胞（M1）标志物的表达相当。同样，S100 A9缺陷影响M2，但不影响M1巨噬细胞体外极化。在急性肾损伤后的修复阶段，S100 A9缺乏影响小鼠中的M2巨噬细胞，导致肾纤维化和损伤。因此，S100 A8/A9在控制巨噬细胞介导的I/R后肾修复中起关键作用。
Upon ischemia/reperfusion (I/R)-induced injury, several damage-associated molecular patterns are expressed including the calcium-binding protein S100A8/A9 complex. S100A8/A9 can be recognized by Toll-like receptor-4 and its activation is known to deleteriously contribute to renal I/R-induced injury. To further test this, wild-type and S100A9 knockout mice (deficient for S100A8/A9 complex) were subjected to renal I/R. The expression of S100A8/A9 was significantly increased 1 day after I/R and was co-localized with Ly6G (mouse neutrophil marker)-positive cells. These knockout mice displayed similar renal dysfunction and damage and neutrophil influx compared with wild-type mice at this early time point. Interestingly, S100A9 knockout mice displayed altered tissue repair 5 and 10 days post I/R, as reflected by increased renal damage, sustained inflammation, induction of fibrosis, and increased expression of collagens. This coincided with enhanced expression of alternatively activated macrophage (M2) markers, while the expression of classically activated macrophage (M1) markers was comparable. Similarly, S100A9 deficiency affected M2, but not M1 macrophage polarization in vitro. During the repair phase following acute kidney injury, S100A9 deficiency affects M2 macrophages in mice leading to renal fibrosis and damage. Thus, S100A8/A9 plays a crucial part in controlling macrophage-mediated renal repair following I/R.