Blockade of the G-CSF Receptor Is Protective in a Mouse Model of Renal Ischemia-Reperfusion Injury
Blockade of the G-CSF Receptor Is Protective in a Mouse Model of Renal Ischemia-Reperfusion Injury
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DOI：
10.4049/jimmunol.2000390
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发表时间：
2020-09-01
影响因子：
4.4
通讯作者：
Pearse, Martin J.
中科院分区：
文献类型：
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作者：
McRae, Jennifer L.;Vikstrom, Ingela B.;Pearse, Martin J.
缺血再灌注损伤(IRI)是一种复杂的炎症过程，严重影响移植器官的功能。中性粒细胞是肾IRI发病的重要因素。G-CSF是中性粒细胞发育、运输和功能的调节因子，在几种中性粒细胞相关的炎症性疾病模型中发挥着关键作用。在这项研究中，我们研究了以中和性中性粒细胞为靶点的G-CSFR单抗在温热肾缺血再灌注小鼠模型中是否可以减少炎症和保护损伤。小鼠在单侧肾缺血22min前24 h给予抗G-CSFR治疗。观察再灌注24 h后肾功能和组织学变化、补体活化、肾损伤标志物和炎症介质的表达。抗G-CSFR对肾脏IRI的保护作用呈剂量依赖关系，显著降低血清肌酐和尿素、肾小管损伤、中性粒细胞和巨噬细胞浸润、补体活化(血浆C5a)和沉积(组织C9)。抗GCSFR可抑制肾组织几种致炎基因(CXCL1/KC、CXCL2/MIP-2、MCP-1/CCL2、CXCR2、IL-6、ICAM-1、P-选择素和C5aR)的表达，同时抑制循环中P-选择素和ICAM-1的水平。在抗G-CSFR治疗的小鼠中，中性粒细胞显示出较低水平的趋化因子受体CXCR2，这与运输到炎症部位的能力降低一致。此外，使用RNA测序的全转录组分析表明，抗G-CSFR治疗后IRI肾脏的基因表达变化与没有IRI的假手术肾脏没有区别。因此，抗G-CSFR治疗阻止了肾脏IRI的发展。我们的结果提示G-CSFR阻断是一种很有前途的减轻肾脏IRI的治疗方法。
Ischemia-reperfusion injury (IRI) is a complex inflammatory process that detrimentally affects the function of transplanted organs. Neutrophils are important contributors to the pathogenesis of renal IRI. Signaling by G-CSF, a regulator of neutrophil development, trafficking, and function, plays a key role in several neutrophil-associated inflammatory disease models. In this study, we investigated whether targeting neutrophils with a neutralizing mAb to G-CSFR would reduce inflammation and protect against injury in a mouse model of warm renal IRI. Mice were treated with anti-G-CSFR 24 h prior to 22-min unilateral renal ischemia. Renal function and histology, complement activation, and expression of kidney injury markers, and inflammatory mediators were assessed 24 h after reperfusion. Treatment with anti-G-CSFR protected against renal IRI in a dose-dependent manner, significantly reducing serum creatinine and urea, tubular injury, neutrophil and macrophage infiltration, and complement activation (plasma C5a) and deposition (tissue C9). Renal expression of several proinflammatory genes (CXCL1/KC, CXCL2/MIP-2, MCP-1/CCL2, CXCR2, IL-6, ICAM-1, P-selectin, and C5aR) was suppressed by anti-GCSFR, as was the level of circulating P-selectin and ICAM-1. Neutrophils in anti-G-CSFR-treated mice displayed lower levels of the chemokine receptor CXCR2, consistent with a reduced ability to traffic to inflammatory sites. Furthermore, whole transcriptome analysis using RNA sequencing showed that gene expression changes in IRI kidneys after anti-G-CSFR treatment were indistinguishable from sham-operated kidneys without IRI. Hence, anti-G-CSFR treatment prevented the development of IRI in the kidneys. Our results suggest G-CSFR blockade as a promising therapeutic approach to attenuate renal IRI.