E-prostanoid 3 receptor deficiency on myeloid cells protects against ischemic acute kidney injury via breaking the auto-amplification loop of necroinflammation.
E-prostanoid 3 receptor deficiency on myeloid cells protects against ischemic acute kidney injury via breaking the auto-amplification loop of necroinflammation.
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DOI：
10.1016/j.kint.2022.08.019
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发表时间：
2022-09
影响因子：
19.6
通讯作者：
J. Leng;Wen Zhao;Jinwei Guo;Gang Yu;Guanghui Zhu;Jiahui Ge;Dong He;Yineng Xu;Xijian Chen-Xijian
中科院分区：
文献类型：
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作者：
J. Leng;Wen Zhao;Jinwei Guo;Gang Yu;Guanghui Zhu;Jiahui Ge;Dong He;Yineng Xu;Xijian Chen-Xijian
坏死性炎症在急性肾损伤（阿基）等疾病中起着重要作用。我们和其他人已经阐明，与炎症密切相关的前列腺素可以在低浓度下激活E-前列腺素3受体（EP 3）。然而，EP 3阻断如何与调节性细胞死亡相互作用并影响阿基仍然未知。在这项研究中，通过在Ep 3敲除（Ep 3-/-）、骨髓嵌合、髓系条件性EP 3敲除和相应对照小鼠中缺血-再灌注（30分钟/24小时）诱导阿基。缺血再灌注后E_2和I_2的产生明显增加，阻断或拮抗EP_3可减轻缺血再灌注损伤。EP 3缺乏抑制了炎性细胞因子释放、中性粒细胞浸润和血清高迁移率族蛋白1水平，但TAK-242的额外TLR 4抑制作用未提供进一步的损伤和炎症保护。Ep 3-/-的保护作用主要通过抑制混合谱系激酶样结构域依赖性坏死性凋亡来介导，这是由于抑制细胞因子产生和通过caspase-8上调将细胞死亡模式从坏死性凋亡转换为凋亡，部分原因是IL-6/JAK 2/STAT 3信号传导的抑制。当坏死性凋亡被抑制时，EP 3缺乏不能进一步减轻损伤。骨髓来源的细胞中的Ep 3-/-，特别是髓样细胞中的Ep 3-/-，保护肾脏的程度与整体EP 3缺失的程度相同。因此，我们的研究结果表明，EP 3缺乏，特别是在骨髓细胞上，通过抑制炎症和打破坏死性炎症的自动放大环来改善缺血性阿基。因此，EP 3可能是预防和/或治疗阿基的有希望的靶点。
Necroinflammation plays an important role in disease settings such as acute kidney injury (AKI). We and others have elucidated that prostaglandins, which are critically involved in inflammation, may activate E-prostanoid 3 receptor (EP3) at low concentrations. However, how EP3 blockade interacts with regulated cell death and affects AKI remains unknown. In this study, AKI was induced by ischemia-reperfusion (30 minutes/24 hours) in Ep3 knockout (Ep3-/-), bone marrow chimeric, myeloid conditional EP3 knockout and corresponding control mice. The production of prostaglandins E2 and I2 was markedly increased after ischemia-reperfusion, and either abrogation or antagonism of EP3 ameliorated the injury. EP3 deficiency curbed inflammatory cytokine release, neutrophil infiltration and serum high-mobility group box 1 levels, but additional TLR4 inhibition with TAK-242 did not offer further protection against the injury and inflammation. The protection of Ep3-/- was predominantly mediated by suppressing Mixed Lineage Kinase domain-Like-dependent necroptosis, resulting from the inhibition of cytokine generation and the switching of cell death modality from necroptosis to apoptosis through caspase-8 up-regulation, in part due to the restraint of IL-6/JAK2/STAT3 signaling. EP3 deficiency failed to further alleviate the injury when necroptosis was inhibited. Ep3-/- in bone marrow-derived cells, particularly that in myeloid cells, protected kidneys to the same extent as that of global EP3 deletion. Thus, our results demonstrate that EP3 deficiency especially that on myeloid cells, ameliorates ischemic AKI via curbing inflammation and breaking the auto-amplification loop of necroinflammation. Hence, EP3 may be a promising target for the prevention and/or treatment of AKI.