IL-17C has a pathogenic role in kidney ischemia/reperfusion injury
IL-17C has a pathogenic role in kidney ischemia/reperfusion injury
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IL-17C 在肾脏缺血/再灌注损伤中具有致病作用
DOI：
10.1016/j.kint.2020.01.015
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发表时间：
2020-06-01
影响因子：
19.6
通讯作者：
Qian, Youcun
中科院分区：
文献类型：
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作者：
Wang, Feng;Yin, Jianyong;Qian, Youcun
在肾缺血/再灌注损伤中，细胞因子是触发炎症反应所必需的。白细胞介素17C(IL-17C)是IL-17家族中唯一的成员，是一种由上皮细胞产生的细胞因子，与宿主防御和自身免疫性疾病有关。然而，对IL-17C在急性肾损伤中的作用知之甚少。我们对此进行了调查，发现患者和急性肾损伤小鼠的肾活检组织中IL-17C显著增加。低氧诱导肾小管上皮细胞IL-17C表达上调为进一步探讨IL-17C的作用，采用小鼠肾脏缺血再灌注损伤模型。用中和抗体或IL-17受体E(IL-17RE)基因敲除抑制IL-17C的作用可减轻肾小管损伤、肾脏氧化应激和肾脏炎症。IL-17C中和和IL-17RE基因敲除均可减轻急性肾损伤小鼠肾脏TH17的活化和IL-17A的表达。IL-17C抗体处理组和IL-17RE基因敲除小鼠的IL-17C下游细胞因子TNF-α和IL-1β水平也降低。此外，用siRNA敲除IL-17C可减少低氧诱导的肾小管细胞炎症，沉默IL-17RE可消除IL-17C在肾小管细胞中的作用。因此，IL-17C可能参与了急性肾损伤的炎症反应，抑制IL-17C或阻断IL-17RE可能是治疗急性肾损伤的新策略。
Cytokines are necessary to trigger the inflammatory response in kidney ischemia/reperfusion injury. Interleukin-17C (IL-17C), a unique member of the IL-17 family, is a cytokine produced by epithelial cells implicated in host defense and autoimmune diseases. However, little is known about the role of IL-17C in acute kidney injury. We investigated this and found that IL-17C was significantly increased in kidney biopsies of patients and mice with acute kidney injury. Exposure to hypoxia induced upregulation of IL-17C in kidney tubular epithelial cells. To further investigate the role of IL-17C, kidney ischemia/reperfusion injury was induced in mice. Inhibition of IL-17C action with a neutralizing antibody or IL-17 receptor E (IL-17RE) knockout attenuated tubular injury, kidney oxidative stress, and kidney inflammation. Mechanistically, both IL-17C neutralization and IL-17RE knockout attenuated TH17 activation and IL-17A expression in kidneys of mice with acute kidney injury. TNF-alpha and IL-1 beta, downstream cytokines of IL-17C, were also reduced in IL-17C antibody pretreated and IL-17RE knockout mice. Additionally, IL-17C knockdown with siRNA decreased hypoxia-induced inflammation in kidney tubular cells and silencing IL-17RE abrogated the effects of IL-17C in kidney tubular cells. Thus, IL-17C may participate in the inflammatory response of acute kidney injury and inhibition of IL-17C or blockade of IL-17 RE may be a novel therapeutic strategy for the treatment of acute kidney injury.