Microglia have been implicated in the pathogenesis of radiation-induced brain injury (RIBI), which severely influences the quality of life during long-term survival. Recently, irradiated microglia were speculated to present an aging-like phenotype. Long noncoding RNAs (lncRNAs) have been recognized to regulate a wide spectrum of biological processes, including senescence; however, their potential role in irradiated microglia remains largely uncharacterized. We used bioinformatics and experimental methods to identify and analyze the senescence phenotype of irradiated microglia. Western blotting, enzyme-linked immunosorbent assays, immunofluorescence, and quantitative real-time reverse transcription-polymerase chain reaction were performed to clarify the relationship between the radiation-induced differentially expressed lncRNAs (RILs) and the distinctive molecular features of senescence in irradiated microglia. We found that the senescence of microglia could be induced using ionizing radiation (IR). A mutual regulation mode existed between RILs and three main features of the senescence phenotype in irradiated microglia: inflammation, the DNA damage response (DDR), and metabolism. Specifically, for inflammation, the expression of two selected RILs (ENSMUST00000190863 and ENSMUST00000130679) was dependent on the major inflammatory signaling pathways of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). The two RILs modulated the activation of NF-κB/MAPK signaling and subsequent inflammatory cytokine secretion. For the DDR, differential severity of DNA damage altered the expression profiles of RILs. The selected RIL, ENSMUST00000130679, promoted the DDR. For metabolism, blockade of sterol regulatory element-binding protein-mediated lipogenesis attenuated the fold-change of several RILs induced by IR. Our findings revealed that certain RILs interacted with senescence in irradiated microglia. RILs actively participated in the regulation of senescence features, suggesting that RILs could be promising intervention targets to treat RIBI.

中文翻译：

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长链非编码 RNA 与受照射小胶质细胞衰老之间的调控耦合

小胶质细胞与辐射性脑损伤 (RIBI) 的发病机制有关，这严重影响了长期生存期间的生活质量。最近，推测受照射的小胶质细胞呈现出类似衰老的表型。长链非编码 RNA (lncRNA) 已被公认为调节广泛的生物过程，包括衰老；然而，它们在受照射的小胶质细胞中的潜在作用在很大程度上仍未得到表征。我们使用生物信息学和实验方法来识别和分析受照射小胶质细胞的衰老表型。蛋白质印迹、酶联免疫吸附测定、免疫荧光、并进行了定量实时逆转录聚合酶链反应，以阐明辐射诱导的差异表达 lncRNA (RIL) 与受照射小胶质细胞衰老的独特分子特征之间的关系。我们发现可以使用电离辐射 (IR) 诱导小胶质细胞的衰老。RILs与受照射小胶质细胞衰老表型的三个主要特征：炎症、DNA损伤反应（DDR）和代谢之间存在相互调节模式。具体而言，对于炎症，两种选定的 RIL（ENSMUST00000190863 和 ENSMUST00000130679）的表达取决于核因子κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）的主要炎症信号通路。这两种 RIL 调节 NF-κB/MAPK 信号的激活和随后的炎性细胞因子分泌。对于 DDR，DNA 损伤的不同严重程度改变了 RIL 的表达谱。选定的 RIL，ENSMUST00000130679，促进了 DDR。对于代谢，甾醇调节元件结合蛋白介导的脂肪生成的阻断减弱了由 IR 诱导的几种 RIL 的倍数变化。我们的研究结果表明，某些 RIL 与受照射的小胶质细胞的衰老相互作用。RILs 积极参与衰老特征的调节，表明 RILs 可能是治疗 RIBI 的有希望的干预目标。甾醇调节元件结合蛋白介导的脂肪生成的阻断减弱了由 IR 诱导的几种 RIL 的倍数变化。我们的研究结果表明，某些 RIL 与受照射的小胶质细胞的衰老相互作用。RILs 积极参与衰老特征的调节，表明 RILs 可能是治疗 RIBI 的有希望的干预目标。甾醇调节元件结合蛋白介导的脂肪生成的阻断减弱了由 IR 诱导的几种 RIL 的倍数变化。我们的研究结果表明，某些 RIL 与受照射的小胶质细胞的衰老相互作用。RILs 积极参与衰老特征的调节，表明 RILs 可能是治疗 RIBI 的有希望的干预目标。