Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury
Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury
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DOI：
10.1681/asn.2014040320
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发表时间：
2015-06-01
影响因子：
13.6
通讯作者：
Bascands, Jean-Loup
中科院分区：
文献类型：
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作者：
Belliere, Julie;Casemayou, Audrey;Bascands, Jean-Loup
横纹肌溶解症如果并发阿基可能危及生命。在甘油诱导的横纹肌溶解后，在大鼠肾脏中观察到巨噬细胞浸润，但巨噬细胞在横纹肌溶解诱导的阿基中的作用仍不清楚。在这里，在一个诊断为横纹肌溶解症的病人，我们检测到大量的巨噬细胞浸润在肾脏。在横纹肌溶解诱导阿基的小鼠模型中，根据疾病的阶段观察到不同的肾巨噬细胞表型。横纹肌溶解后2天，F4/80（低）CD 11b（高）Ly 6 b（高）CD 206（低）肾巨噬细胞占优势，而到第8天，F4/80（高）CD 11b（+）Ly 6 b（低）CD 206（高）细胞变得最丰富。流式细胞仪分选的巨噬细胞的单细胞基因表达分析显示，这些亚群是异质性的，单个细胞同时表达M1和M2标记。脂质体氯膦酸盐介导的巨噬细胞耗竭显著降低了F4/80（低）CD 11b（高）Ly 6 b（高）CD 206（低）巨噬细胞的早期浸润。此外，转录调控的目标可能参与疾病的进展，包括纤连蛋白，胶原蛋白III，和化学引诱物，通过单细胞分析，被证实为巨噬细胞依赖性原位。在体外，肌红蛋白治疗诱导近端肾小管细胞分泌趋化因子和巨噬细胞表达促炎标志物。在第30天，脂质体氯膦酸盐介导的巨噬细胞耗竭减少了纤维化，并改善了肾修复和小鼠存活。横纹肌溶解症后7个月，组织学病变仍然存在，但随着巨噬细胞的预先消耗而显著减少。这些结果表明，巨噬细胞在横纹肌溶解诱导的阿基进展中起重要作用，并提倡对患有这种疾病的患者进行长期随访。
Rhabdonnyolysis can be life threatening if complicated by AKI. Macrophage infiltration has been observed in rat kidneys after glycerol-induced rhabdomyolysis, but the role of macrophages in rhabdomyolysis-induced AKI remains unknown. Here, in a patient diagnosed with rhabdomyolysis, we detected substantial macrophage infiltration in the kidney. In a mouse model of rhabdomyolysis-induced AKI, diverse renal macrophage phenotypes were observed depending on the stage of the disease. Two days after rhabdomyolysis, F4/80(low)CD11b(high)Ly6b(high)CD206(low) kidney macrophages were dominant, whereas by day 8, F4/80(high)CD11b(+)Ly6b(low)CD206(high) cells became the most abundant. Single-cell gene expression analyses of FACS-sorted macrophages revealed that these subpopulations were heterogeneous and that individual cells simultaneously expressed both M1 and M2 markers. Liposomal clodronate-mediated macrophage depletion significantly reduced the early infiltration of F4/80(low)CD11b(high)Ly6b(high)CD206(low) macrophages. Furthermore, transcriptionally regulated targets potentially involved in disease progression, including fibronectin, collagen III, and chemoattractants that were identified via single-cell analysis, were verified as macrophage-dependent in situ. In vitro, myoglobin treatment induced proximal tubular cells to secrete chemoattractants and macrophages to express proinflammatory markers. At day 30, liposomal clodronate-mediated macrophage depletion reduced fibrosis and improved both kidney repair and mouse survival. Seven months after rhabdomyolysis, histologic lesions were still present but were substantially reduced with prior depletion of macrophages. These results suggest an important role for macrophages in rhabdomyolysis-induced AKI progression and advocate the utility of long-term follow-up for patients with this disease.