Introduction: Acute kidney injury (AKI) is one of the most common causes of organ failure in critically ill patients. Following AKI, the canonical pro-inflammatory cytokine interleukin-1β (IL-1β) is released predominantly from activated myeloid cells and binds to the interleukin-1 receptor R1 (IL-1R1) on leukocytes and kidney parenchymal cells. IL-1R1 on kidney tubular cells is known to amplify the immune response and exacerbate AKI. However, the specific role of IL-1R1 on myeloid cells during AKI is poorly understood. The objective of the present study was to elucidate the function of myeloid cell IL-1R1 during AKI. As IL-1R1 is known to signal through the pro-inflammatory Toll-like receptor (TLR)/MyD88 pathway, we hypothesized that myeloid cells expressing IL-1R1 would exacerbate AKI.Methods: IL-1R1 was selectively depleted in CD11c+-expressing myeloid cells with CD11cCre+/IL-1R1fl/fl (Myel KO) mice. Myel KO and littermate controls (CD11cCre-/IL-1R1fl/fl–Myel WT) were subjected to kidney ischemia/reperfusion (I/R) injury. Kidney injury was assessed by blood urea nitrogen (BUN), serum creatinine and injury marker neutrophil gelatinase-associated lipocalin (NGAL) protein expression. Renal tubular cells (RTC) were co-cultured with CD11c+ bone marrow-derived dendritic cells (BMDC) from Myel KO and Myel WT mice.Results: Surprisingly, compared to Myel WT mice, Myel KO mice displayed exaggerated I/R-induced kidney injury, as measured by elevated levels of serum creatinine and BUN, and kidney NGAL protein expression. In support of these findings, in vitro co-culture studies showed that RTC co-cultured with Myel KO BMDC (in the presence of IL-1β) exhibited higher mRNA levels of the kidney injury marker NGAL than those co-cultured with Myel WT BMDC. In addition, we observed that IL-1R1 on Myel WT BMDC preferentially augmented the expression of anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra/Il1rn), effects that were largely abrogated in Myel KO BMDC. Furthermore, recombinant IL-1Ra could rescue IL-1β-induced tubular cell injury.Discussion: Our findings suggest a novel function of IL-1R1 is to serve as a critical negative feedback regulator of IL-1 signaling in CD11c+ myeloid cells to dampen inflammation to limit AKI. Our results lend further support for cell-specific, as opposed to global, targeting of immunomodulatory agents.

中文翻译：

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缺血性 AKI 后肾髓细胞中 IL-1 受体的新抗炎作用

简介：急性肾损伤（AKI）是危重患者器官衰竭的最常见原因之一。 AKI 后，典型的促炎细胞因子白细胞介素 1β (IL-1β) 主要从活化的骨髓细胞中释放，并与白细胞和肾实质细胞上的白细胞介素 1 受体 R1 (IL-1R1) 结合。已知肾小管细胞上的 IL-1R1 会增强免疫反应并加剧 AKI。然而，AKI 期间 IL-1R1 对骨髓细胞的具体作用尚不清楚。本研究的目的是阐明 AKI 期间骨髓细胞 IL-1R1 的功能。由于已知 IL-1R1 通过促炎 Toll 样受体 (TLR)/MyD88 通路发出信号，因此我们假设表达 IL-1R1 的骨髓细胞会加剧 AKI。方法：IL-1R1 在 CD11c 中选择性缺失+-表达骨髓细胞CD11cCre+/IL-1R1液量/液量(Myel KO) 小鼠。 Myel KO 和同窝对照（CD11cCre-/IL-1R1液量/液量–Myel WT）遭受肾脏缺血/再灌注（I/R）损伤。通过血尿素氮（BUN）、血清肌酐和损伤标志物中性粒细胞明胶酶相关脂质运载蛋白（NGAL）蛋白表达来评估肾损伤。肾小管细胞 (RTC) 与 CD11c 共培养+来自 Myel KO 和 Myel WT 小鼠的骨髓源性树突状细胞 (BMDC)。结果：令人惊讶的是，与 Myel WT 小鼠相比，Myel KO 小鼠表现出过度的 I/R 诱导的肾损伤，通过血清肌酐和 BUN 水平升高来衡量和肾脏 NGAL 蛋白表达。为了支持这些发现，体外共培养研究表明，与 Myel KO BMDC 共培养（存在 IL-1β）的 RTC 表现出比与 Myel WT BMDC 共培养的肾损伤标志物 NGAL 的 mRNA 水平更高。此外，我们观察到 Myel WT BMDC 上的 IL-1R1 优先增强抗炎细胞因子白细胞介素 1 受体拮抗剂（IL-1ra/伊尔恩），在 Myel KO BMDC 中大部分被废除的效果。此外，重组IL-1Ra可以挽救IL-1β诱导的肾小管细胞损伤。讨论：我们的研究结果表明IL-1R1的一个新功能是作为CD11c中IL-1信号传导的关键负反馈调节剂+骨髓细胞抑制炎症以限制 AKI。我们的结果进一步支持细胞特异性（而不是全局）靶向免疫调节剂。