Interleukin 1 receptor (IL-1R1) activation exacerbates toxin-induced acute kidney injury
Interleukin 1 receptor (IL-1R1) activation exacerbates toxin-induced acute kidney injury
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DOI：
10.1152/ajprenal.00104.2018
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发表时间：
2018-09-01
影响因子：
4.2
通讯作者：
Crowley, Steven D.
中科院分区：
文献类型：
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作者：
Privratsky, Jamie R.;Zhang, Jiandong;Crowley, Steven D.
急性肾损伤（AKI）是发病率和死亡率的主要原因。药物性/毒性AKI可由多种治疗药物引起。顺铂是一种有效的化疗药物，其给药受到显著肾毒性的限制。目前缺乏预防顺铂诱导AKI的治疗方法。尽管肿瘤坏死因子- α (TNF)在顺铂肾毒性的发病机制中起着关键作用，但在这种情况下触发TNF生成的先天免疫信号通路需要阐明。在这方面，无菌损伤触发了白细胞介素(IL)-1、IL-1 α和IL-1 β两种亚型的释放和激活。反过来，这些配体刺激白细胞介素-1受体（IL-1R1）参与促炎信号级联，诱导TNF诱导。因此，我们假设IL-1R1激活通过诱导TNF产生加重顺铂诱导的AKI，从而增强肾实质细胞和浸润性髓细胞之间的炎症信号。IL-1R1 +/+ (WT)和IL-1R1 -/- (KO)小鼠遭受顺铂诱导的AKI。与WT小鼠相比，IL-1R1 KO小鼠的血清肌酐、BUN、肾脏NGAL mRNA水平和肾病理的盲法组织学分析均显示AKI减轻。在顺铂损伤的肾脏中，IL-1R1 KO小鼠全肾TNF水平降低，表达ly6g的中性粒细胞减少。此外，对肾内免疫细胞的无偏倚机器学习分析显示，与IL-1R1 WT肾脏相比，IL-1R1 KO损伤肾脏中CD11b(int)/CD11c（int）髓样细胞数量减少。顺铂治疗后，与WTs相比，IL-1R1 KO肾脏产生的tnf更少：巨噬细胞、CD11b(int)/CD11c（int）细胞和中性粒细胞，这与IL-1R1使肾内骨髓细胞向促炎表型极化的作用一致。阻断il -1依赖的信号通路以降低顺铂治疗期间的肾毒性值得进一步评估。
Acute kidney injury (AKI) is a leading cause of morbidity and mortality. Drug-induced/toxic AKI can be caused by a number of therapeutic agents. Cisplatin is an effective chemotherapeutic agent whose administration is limited by significant nephrotoxicity. Therapies to prevent cisplatin-induced AKI are lacking. Although tumor necrosis factor-alpha (TNF) plays a key role in the pathogenesis of cisplatin nephrotoxicity, the innate immune signaling pathways that trigger TNF generation in this context require elucidation. In this regard, sterile injury triggers the release and activation of both isoforms of interleukin(IL)-1, IL-1 alpha and IL-1 beta. In turn, stimulation of the interleukin-1 receptor (IL-1R1) by these ligands engages a proinflammatory signaling cascade that induces TNF induction. We therefore hypothesized that IL-1R1 activation exacerbates cisplatin-induced AKI by inducing TNF production, thereby augmenting inflammatory signals between kidney parenchymal cells and infiltrating myeloid cells. IL-1R1 +/+ (WT) and IL-1R1 -/- (KO) mice were subjected to cisplatin-induced AKI. Compared with WT mice, IL-1R1 KO mice had attenuated AKI as measured by serum creatinine and BUN, renal NGAL mRNA levels, and blinded histological analysis of kidney pathology. In the cisplatin-injured kidney, IL-1R1 KO mice had diminished levels of whole kidney TNF, and fewer Ly6G-expressing neutrophils. In addition, an unbiased machine learning analysis of intrarenal immune cells revealed a diminished number of CD11b(int)/CD11c(int) myeloid cells in IL-1R1 KO injured kidneys compared with IL-1R1 WT kidneys. Following cisplatin, IL-1R1 KO kidneys, compared with WTs, had fewer TNF-producing: macrophages, CD11b(int)/CD11c(int) cells, and neutrophils, consistent with an effect of IL-1R1 to polarize intrarenal myeloid cells toward a proinflammatory phenotype. Interruption of IL-1-dependent signaling pathways warrants further evaluation to decrease nephrotoxicity during cisplatin therapy.