Knockout of the interleukin-36 receptor protects against renal ischemia-reperfusion injury by reduction of proinflammatory cytokines
Knockout of the interleukin-36 receptor protects against renal ischemia-reperfusion injury by reduction of proinflammatory cytokines
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DOI：
10.1016/j.kint.2017.09.017
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发表时间：
2018-03-01
影响因子：
19.6
通讯作者：
Terada, Yoshio
中科院分区：
文献类型：
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作者：
Nishikawa, Hirofumi;Taniguchi, Yoshinori;Terada, Yoshio
IL-36 是 IL-1 细胞因子家族的新成员，包括 3 种异构体：IL-36 α、IL-36 β 和 IL-36 γ，所有异构体均与含有 IL-36 受体 (IL-36R) 的异二聚体结合。关于 IL-36 轴在急性肾损伤 (AKI) 发病机制中的作用知之甚少。因此，我们使用 IL-36R 敲除小鼠和野生型小鼠评估了 IL-36 在 AKI 双侧肾缺血再灌注损伤模型中的功能。 IL-36R被发现在肾脏中表达，主要在近端肾小管中表达。 IL-36R敲除小鼠缺血再灌注损伤后血浆肌酐、血尿素氮和IL-6水平显着低于野生型小鼠。免疫组织学分析显示轻度肾小管损伤。缺血再灌注损伤后IL-36α/β/γ水平升高，且IL-36α在淋巴细胞和近端肾小管细胞中表达，但IL-36R敲除小鼠缺血再灌注损伤后IL-6和TNF-α的mRNA水平较低。在肾小管上皮细胞的原代培养物中，IL-36 α 处理上调 NF-κ B 活性和 Erk 磷酸化。值得注意的是，在 AKI 患者中，尿液 IL-36 α 水平升高，肾活检样本中 IL-36 α 染色增强。因此，IL-36α/IL-36R 阻断可以作为 AKI 的潜在治疗靶点。
IL-36, a newly named member of the IL-1 cytokine family, includes 3 isoforms, IL-36 alpha, IL-36 beta, and IL-36 gamma, all of which bind to a heterodimer containing the IL-36 receptor (IL-36R). Little is known about the role of the IL-36 axis in acute kidney injury (AKI) pathogenesis. Therefore, we evaluated IL-36 function in the bilateral renal ischemia-reperfusion injury model of AKI using IL-36R knockout and wild-type mice. IL-36R was found to be expressed in the kidney, mainly in proximal tubules. In IL-36R knockout mice, plasma creatinine, blood urea nitrogen, and IL-6 levels after ischemia-reperfusion injury were significantly lower than those in wild-type mice. Immunohistological analysis revealed mild tubular injury. IL-36 alpha/beta/gamma levels were increased after ischemia-reperfusion injury, and IL-36 alpha was expressed in lymphocytes and proximal tubular cells, but post-ischemia-reperfusion injury mRNA levels of IL-6 and TNF-alpha were low in IL-36R knockout mice. In primary cultures of renal tubular epithelial cells, IL-36 alpha treatment upregulated NF-kappa B activity and Erk phosphorylation. Notably, in patients with AKI, urine IL-36 alpha levels were increased, and IL-36 alpha staining in renal biopsy samples was enhanced. Thus, IL-36 alpha/IL-36R blockage could serve as a potential therapeutic target in AKI.