The Atypical Chemokine Receptor 2 Limits Progressive Fibrosis after Acute Ischemic Kidney Injury
The Atypical Chemokine Receptor 2 Limits Progressive Fibrosis after Acute Ischemic Kidney Injury
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DOI：
10.1016/j.ajpath.2018.09.016
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发表时间：
2019-02-01
影响因子：
6
通讯作者：
Vielhauer, Volker
中科院分区：
文献类型：
--
作者：
Lux, Moritz;Blaut, Alexander;Vielhauer, Volker
肾缺血再灌注损伤（IRI）后，炎症的消退允许肾小管再生，而持续的由白细胞浸润介导的炎症损伤导致肾单位损失和肾纤维化，这是慢性肾脏疾病的典型特征。非典型趋化因子受体2 （ACKR2）是一种趋化因子诱饵受体，结合并清除炎性CC趋化因子并减少局部白细胞积聚。我们假设ACKR2限制了肾IRI后的白细胞浸润、炎症和纤维化组织重塑，从而阻止了慢性肾脏疾病的发展。与野生型相比，Ackr2缺陷增加了体外肿瘤坏死因子刺激的小管间质组织中CC趋化因子配体2的水平。在瞬时肾蒂夹紧后1或5天发生早期IRI的Ackr2缺陷小鼠中，小管损伤与野生型相似，尽管在缺血后Ackr2（-/-）肾脏中单核吞噬细胞的积累增加。关于长期结果，Ackr2（-/-）肾在IRI后5周表现出更多的肾小管损伤，这与单核吞噬细胞、T细胞、Ly6Chi9h炎性巨噬细胞和炎症的持续增加有关。此外，Ackr2缺乏导致IRI后5周Ackr2（-/-）肾脏的肾纤维化显著加重，表现为基质分子表达增加，a-平滑肌肌动蛋白阳性肌成纤维细胞和骨髓源性纤维细胞在肾脏积聚。ACKR2在限制缺血性急性肾损伤后的持续炎症、肾小管丢失和肾纤维化方面发挥重要作用，因此可以防止进展为慢性肾脏疾病。
Following renal ischemia-reperfusion injury (IRI), resolution of inflammation allows tubular regeneration, whereas ongoing inflammatory injury mediated by infiltrating leukocytes leads to nephron loss and renal fibrosis, typical hallmarks of chronic kidney disease. Atypical chemokine receptor 2 (ACKR2) is a chemokine decoy receptor that binds and scavenges inflammatory CC chemokines and reduces local leukocyte accumulation. We hypothesized that ACKR2 limits leukocyte infiltration, inflammation, and fibrotic tissue remodeling after renal IRI, thus preventing progression to chronic kidney disease. Compared with wild type, Ackr2 deficiency increases CC chemokine ligand 2 levels in tumor necrosis factor stimulated tubulointerstitial tissue in vitro. In Ackr2-deficient mice with early IRI 1 or 5 days after transient renal pedicle clamping, tubular injury was similar to wild type, although accumulation of mononuclear phagocytes increased in postischemic Ackr2(-/-) kidneys. Regarding long-term outcomes, Ackr2(-/-) kidneys displayed more tubular injury 5 weeks after IRI, which was associated with persistently increased renal infiltrates of mononuclear phagocytes, T cells, Ly6Chi9h inflammatory macrophages, and inflammation. Moreover, Ackr2 deficiency caused substantially aggravated renal fibrosis in Ackr2(-/-) kidneys 5 weeks after IRI, shown by increased expression of matrix molecules, renal accumulation of a-smooth muscle actin positive myofibroblasts, and bone marrow derived fibrocytes. ACKR2 is important in limiting persistent inflammation, tubular loss, and renal fibrosis after ischemic acute kidney injury and, thus, can prevent progression to chronic renal disease.