Onset, progression and cardiovascular outcome of chronic kidney disease (CKD) are influenced by the concomitant sterile inflammation. The pro-inflammatory cytokine family interleukin (IL)-1 is crucial in CKD with the key alarmin IL-1α playing an additional role as an adhesion molecule that facilitates immune cell tissue infiltration and consequently inflammation. Here, we investigate calcium ion and reactive oxygen species (ROS)-dependent regulation of different aspects of IL-1α-mediated inflammation. We show that human CKD monocytes exhibit altered purinergic calcium ion signatures. Monocyte IL-1α release was reduced when inhibiting P2X7, and to a lesser extent P2X4, two ATP-receptors that were found upregulated compared to monocytes from healthy people. In murine CKD models, deleting P2X7 (P2X7-/-) abolished IL-1α release but increased IL-1α surface presentation by bone marrow derived macrophages and impaired immune cell infiltration of the kidney without protecting kidney function. In contrast, immune cell infiltration into injured wild type and P2X7-/- hearts was comparable in a myocardial infarction model, independent of previous kidney injury. Both the chimeric mouse line harboring P2X7-/- immune cells in wild type recipient mice, and the inversely designed chimeric line showed less acute inflammation. However, only the chimera harboring P2X7-/- immune cells showed a striking resistance against injury-induced cardiac remodeling. Mechanistically, ROS measurements reveal P2X7-induced mitochondrial ROS as an essential factor for IL-1α release by monocytes. Our studies uncover a dual role of P2X7 in regulating IL-1α biogenesis with consequences for inflammation and inflammation-induced deleterious cardiac remodeling that may determine clinical outcomes in CKD therapies.

中文翻译：

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嘌呤能受体 P2X7 以活性氧依赖性方式调节慢性肾病中白细胞介素-1α 介导的炎症


慢性肾脏病 （CKD） 的发病、进展和心血管结局受伴随的无菌性炎症的影响。促炎细胞因子家族白细胞介素 （IL）-1 在 CKD 中至关重要，关键警报蛋白 IL-1α 作为粘附分子发挥额外作用，促进免疫细胞组织浸润，从而促进炎症。在这里，我们研究了钙离子和活性氧 （ROS） 依赖性对 IL-1α 介导的炎症不同方面的调节。我们表明人 CKD 单核细胞表现出改变的嘌呤能钙离子特征。抑制 P2X7 时，单核细胞 IL-1α 的释放减少，P2X4 的释放程度较小，与健康人的单核细胞相比，这两种 ATP 受体被发现上调。在小鼠 CKD 模型中，删除 P2X7 （P2X7-/-） 消除了 IL-1α 的释放，但增加了骨髓来源的巨噬细胞对 IL-1α 的表面呈递，并损害了免疫细胞对肾脏的浸润，而没有保护肾功能。相比之下，免疫细胞浸润到受伤野生型和 P2X7-/-心脏在心肌梗死模型中是相当的，与既往肾损伤无关。野生型受体小鼠中含有 P2X7-/-免疫细胞的嵌合小鼠系和逆向设计的嵌合系均显示出较少的急性炎症。然而，只有携带 P2X7-/-免疫细胞的嵌合体对损伤诱导的心脏重塑表现出惊人的抵抗力。从机制上讲，ROS 测量显示 P2X7 诱导的线粒体 ROS 是单核细胞释放 IL-1α 的重要因子。 我们的研究揭示了 P2X7 在调节 IL-1α 生物发生中的双重作用，对炎症和炎症诱导的有害心脏重塑产生影响，这可能决定 CKD 治疗的临床结果。