Regulatory coupling between long noncoding RNAs and senescence in irradiated microglia

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Microglia as Therapeutic Target for Radiation-Induced Brain Injury

“…DNA damage caused by IR is an important activator of microglia. High LET directly ionizes DNA molecules, while low LET tends to indirectly damage DNA through ROS and free radicals originating from water radiolysis [ 6 , 66 , 67 ]. Damaged DNA can quickly trigger the activation of transcription factors such as nuclear factor κB (NF-κB), cAMP response element-binding protein (CREB), and activating protein 1 (AP-1), which control intracellular ROS generation and gene expression of inflammatory factors including IL-1β, TNF-α, cyclooxygenase 2 (COX-2), and monocyte chemoattractant protein-1 (MCP-1/CCL2) [ 18 , 68 ].…”

“…Such structural diversity contributes to extensive interactions between lncRNA and proteins, DNA, or RNA, which consequently change cellular and molecular functions and affect the disease process [ 239 , 240 ]. Xu et al showed increased levels of LncRNA ENSMUST00000190863 and ENSMUST00000130679 in BV-2 cells, as well as in primary microglial cells isolated from the hippocampus of mice at 24 h after 10 Gy X-ray radiation [ 66 ]. Through siRNA transfection, they demonstrated that increased ENSMUST00000190863 or ENSMUST00000130679 in microglia promoted DNA damage (DDR) and phosphorylation of p65, JNK, and p38, as well as subsequent downstream pro-inflammatory cytokine release after radiation, which resulted in apoptosis of co-cultured neural stem cells [ 66 ].…”

“…Xu et al showed increased levels of LncRNA ENSMUST00000190863 and ENSMUST00000130679 in BV-2 cells, as well as in primary microglial cells isolated from the hippocampus of mice at 24 h after 10 Gy X-ray radiation [ 66 ]. Through siRNA transfection, they demonstrated that increased ENSMUST00000190863 or ENSMUST00000130679 in microglia promoted DNA damage (DDR) and phosphorylation of p65, JNK, and p38, as well as subsequent downstream pro-inflammatory cytokine release after radiation, which resulted in apoptosis of co-cultured neural stem cells [ 66 ]. Moreover, radiation increased lipid droplet accumulation within microglia, and almost one-third of the metabolism-associated genes of ENSMUST00000190863 and ENSMUST00000130679 downstream are related to lipid metabolism, raising the possibility of adipogenesis regulation by them.…”

Senescent Microglia: The Key to the Ageing Brain?

“…However, this is perhaps not the most representative model of how microglial senescence might arise in the majority of individuals as part of the normal ageing process. The use of ionising radiation to induce senescence presents a similar quandary [ 185 ].…”

Ionizing Radiation-Induced Brain Cell Aging and the Potential Underlying Molecular Mechanisms

“…Activated microglia exhibit a neurotoxic phenotype and can cause neuronal damage and death. This phenotype has been implicated in various neurodegenerative diseases, radiation-induced brain injury, and brain aging [ 47 , 56 ]. Several features of this neurotoxic phenotype resemble those of aging.…”