Role of cyclooxygenases in neuroinflammation

环氧合酶在神经炎症中的作用

• 批准号: 7963968
• 负责人: Francesca Bosetti
• 金额: $ 32.69万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7963968
• 关键词: Address; Alzheimer' s Disease; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Attenuated; Bacterial Meningitis; Blood - brain barrier anatomy; Blood Vessels; Brain; Cells; Coxibs; Free Radicals; Gelatinase B; Gene Expression; Hippocampus (Brain); Immune; Immune response; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Learning; Leukocytes; Lipopolysaccharides; Magnetic Resonance Imaging; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Memory; Metabolism; Microarray Analysis; Microglia; Modeling; Multiple Sclerosis; Mus; Neuraxis; Neurodegenerative Disorders; Neuronal Injury; Nitric Oxide; Nitrogen; Ontology; Oxygen; PTPRC gene; Pan Genus; Parkinson Disease; Pathogenesis; Peripheral; Permeability; Pharmaceutical Preparations; Physiological; Prevention strategy; Process; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Proteins; Reaction; Reporting; Ribosomes; Role; Secondary to; Signal Pathway; Site; Stroke; Stromelysin 1; Therapeutic; Vascular Permeabilities; Wild Type Mouse; attenuation; brain tissue; chemokine; cyclooxygenase 1; cyclooxygenase 2; cytokine; cytotoxic; in vivo; mRNA Expression; migration; neuroinflammation; oxidation; oxidative damage; response; toll-like receptor 4

Using microarray technology, we reported that our model of intracerebroventricular injection of lipopolysaccharide (LPS) results in a robust inflammatory response in the brain, with an increased expression of Gene Ontology (GO) terms for inflammation and the ribosome and a decreased expression of GO terms associated with learning and memory. We showed that cyclooxygenase (COX)-1-/- mice have a significant reduction in brain inflammatory response and oxidative damage after LPS. The protection was attributed to attenuation of microglial activation, a critical process in the initiation of inflammation, and to a reduction of inflammatory mediators such as prostaglandins, cytokines, chemokines and of protein oxidation, critical factors contributing to the secondary progression of the inflammatory reaction and oxidative damage. Peripheral leukocyte recruitment in neuroinflammatory conditions can exacerbate brain tissue damage by releasing cytotoxic mediators and by increasing vascular permeability. Since chemokines are involved in leukocyte recruitment into the inflamed brain, we hypothesized that COX-1 and COX-2 deletion will differentially modulate blood-brain barrier (BBB) permeability in response to LPS. Using quantitative magnetic resonance imaging, we found that LPS-induced BBB disruption was exacerbated in COX-2-/- vs. COX-2+/+ mice. In the hippocampus and cortex of LPS-treated mice, matrix metalloproteinase (MMP)-3 activity was significantly decreased in COX-1-/- mice, whereas in COX-2-/- mice the activity of both MMP-9 and MMP-3, known to mediate BBB breakdown, was increased. Brain mRNA expression of the leukocyte attracting chemokine Cxcl10, the intercellular interaction molecule Icam-1, the pan-leukocyte marker cd45 was increased in COX-2-/- vs. COX-2+/+ mice, whereas cxcl10 and cd45 mRNA expressions were decreased in COX-1-/- vs. COX-1+/+ mice after LPS. COX-derived prostaglandins promote the migration of several immune cells in vitro, however, the specific roles of COX-1 and -2 on leukocyte recruitment in vivo have not been investigated. To examine the specific effects of COX-1 or COX-2 deficiency on neuroinflammation-induced leukocyte infiltration, we used a model of LPS-induced innate immune activation in COX-1-/-, COX-2-/-, and their respective wild-type mice. After LPS, leukocyte infiltration and inflammatory response were attenuated in COX-1-/- and increased in COX-2-/- mice, compared to their respective wild-type controls. This influx of leukocytes was accompanied by a marked disruption of blood-brain barrier and differential expression of chemokines. These results indicate that COX-1 and COX-2 differentially modulate leukocyte recruitment and BBB permeability during toll-like receptor 4-dependent innate immune activation, and suggest that inhibition of COX-1 activity is beneficial, whereas COX-2 inhibition may be detrimental, during a primary neuroinflammatory response.

使用微阵列技术，我们报告说，我们的脑室内注射脂多糖（LPS）的模型会导致大脑的强烈炎症反应，炎症和核糖体的基因本学（GO）表达增加，核糖体和核糖体的表达以及与学习和记忆相关的GO表达的降低。我们表明，环氧合酶（COX）-1 - / - 小鼠的脑炎症反应和LPS后氧化损伤显着降低。保护归因于小胶质细胞激活的衰减，炎症引发的关键过程以及炎症介质的减少，例如前列腺素，细胞因子，趋化因子和蛋白质氧化，关键因素有助于炎症反应和氧化损伤的二次进展。神经炎症条件下的周围白细胞募集会通过释放细胞毒性介质和增加血管渗透性来加剧脑组织损伤。由于趋化因子参与白细胞募集到发炎的大脑中，我们假设COX-1和COX-2缺失将响应LPS差异地调节血脑屏障（BBB）渗透率。使用定量磁共振成像，我们发现LPS诱导的BBB破坏在COX-2 - / - 与Cox-2+/+小鼠中加剧。在LPS处理的小鼠的海马和皮质中，基质金属蛋白酶（MMP）-3在COX-1-/ - 小鼠中显着降低了活性，而在COX-2 - / - 小鼠中，MMP-9和MMP-3的活性都会增加，已知介导BBB的衰减，增加了。白细胞的脑mRNA表达吸引趋化因子CXCL10，细胞间相互作用分子ICAM-1，Cox-2 - / - vs. Cox-2+/+小鼠中泛白细胞标记CD45增加，而Cox-cxcl10和CD45 mRNA表达在Cox-1 - /-Vs.-vs.-vs.-vs.-vs.-+/+ lps中降低了CXCL10和CD45 mRNA表达。 Cox衍生的前列腺素在体外促进了几种免疫细胞的迁移，但是，尚未研究Cox-1和-2在体内白细胞募集中的特定作用。为了检查COX-1或COX-2缺乏症对神经炎症引起的白细胞浸润的特定影响，我们使用了LPS诱导的COX-1 - / - ，COX-2 - / - 及其各自的野生型小鼠中的LPS诱导的先天免疫激活模型。 LPS之后，与各自的野生型对照相比，在COX-1 - / - 中减弱白细胞浸润和炎症反应在COX-1 - / - 中增加。白细胞的这种涌入伴随着明显的血脑屏障和趋化因子差异表达的破坏。这些结果表明，在Toll样受体4依赖性的先天免疫激活期间，COX-1和COX-COX-1和COX差异调节白细胞的募集和BBB渗透性，并表明在原代神经发作响应期间，Cox-2抑制COX-1的抑制是有益的，而COX-2抑制可能是有害的。