Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model.
Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model.
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DOI：
10.1155/2022/2479626
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发表时间：
2022
影响因子：
--
通讯作者：
Sabir H
中科院分区：
文献类型：
--
作者：
Bernis ME;Schleehuber Y;Zweyer M;Maes E;Felderhoff-Müser U;Picard D;Sabir H
缺氧缺血性脑病（HIE）主要影响早产儿和足月新生儿，导致脑损伤的风险很高。同时存在的感染/炎症和出生窒息是与HIE相关的脑内促炎细胞因子增加相关的关键因素。小胶质细胞是围产期脑损伤过程中炎症的关键介质，其特征在于其表型可塑性，这可能有助于它们参与损伤诱导的炎症的进展和消退。本研究的目的是研究与促炎和抗炎细胞因子以及核苷酸结合结构域，富含亮氨酸的重复蛋白（NLRP-3）的小胶质细胞炎性体相关的基因的时间表达。为此，我们使用我们建立的新生大鼠模型的炎症致敏缺氧缺血性（HI）脑损伤在7天的大鼠。我们使用实时PCR评估了11种细胞因子和NLRP-3的基因表达谱，这些细胞因子和NLRP-3来自在不同时间点（LPS注射后3.5小时和HI后0、5、24、48和72小时）的脑样品的分选的CD 11b/c小胶质细胞，这些时间点在不同处理之后：大肠杆菌脂多糖（LPS）、媒介物/HI和LPS/HI。我们的研究结果表明，小胶质细胞是炎症反应的早期关键介质，并加剧HI后的炎症反应，在HI后的早期极化为主要的促炎M1表型。仅暴露于HI的脑显示促炎细胞因子的表达延迟。我们还证明了NLRP-3在HI损伤后以高表达在炎症消退中起作用。两者的组合，感染前/炎症条件和缺氧缺血，导致更高的促炎细胞因子风暴，突出急性炎症致敏前缺氧损伤的围产期脑损伤的严重程度的显着贡献。
Hypoxic-ischemic encephalopathy (HIE) mainly affects preterm and term newborns, leading to a high risk of brain damage. Coexisting infection/inflammation and birth asphyxia are key factors associated with intracerebral increase of proinflammatory cytokines linked to HIE. Microglia are key mediators of inflammation during perinatal brain injury, characterized by their phenotypic plasticity, which may facilitate their participation in both the progression and resolution of injury-induced inflammation. The purpose of this study was to investigate the temporal expression of genes associated with pro- and anti-inflammatory cytokines as well as the nucleotide-binding domain, leucine-rich repeat protein (NLRP-3) inflammasome from microglia cells. For this purpose, we used our established neonatal rat model of inflammation-sensitized hypoxic-ischemic (HI) brain injury in seven-day-old rats. We assessed gene expression profiles of 11 cytokines and for NLRP-3 using real-time PCR from sorted CD11b/c microglia of brain samples at different time points (3.5 h after LPS injection and 0, 5, 24, 48, and 72 hours post HI) following different treatments: vehicle, E. coli lipopolysaccharide (LPS), vehicle/HI, and LPS/HI. Our results showed that microglia are early key mediators of the inflammatory response and exacerbate the inflammatory response following HI, polarizing into a predominant proinflammatory M1 phenotype in the early hours post HI. The brains only exposed to HI showed a delay in the expression of proinflammatory cytokines. We also demonstrated that NLRP-3 plays a role in the inflammatory resolution with a high expression after HI insult. The combination of both, a preinfection/inflammation condition and hypoxia-ischemia, resulted in a higher proinflammatory cytokine storm, highlighting the significant contribution of acute inflammation sensitizing prior to a hypoxic insult on the severity of perinatal brain damage.
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