Immunomodulation of white matter integrity after stroke

中风后白质完整性的免疫调节

• 批准号: 9243323
• 负责人: Xiaoming Hu
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243323
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Attenuated; Axon; Behavior; Biological Process; Brain; Brain region; Cell Differentiation process; Cell Maturation; Coculture Techniques; Cognitive; Cognitive deficits; Corpus Callosum; Corpus striatum structure; Data; Demyelinations; Development; Dichloromethylene Diphosphonate; Disease; Endothelin-1; Exhibits; External Capsule; Failure; Future; Generations; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukin-10; Interleukin-14; Interleukin-4; Internal Capsule; Intranasal Administration; Intraventricular Infusion; Ischemia; Ischemic Stroke; Knockout Mice; Liposomes; Long-Term Effects; Mediating; Microglia; Microinjections; Middle Cerebral Artery Occlusion; Modeling; Mus; Myelin Basic Proteins; Myelin Sheath; Neuroglia; Neurologic Deficit; Neurological outcome; Neurons; Oligodendroglia; Outcome; PPAR alpha; PPAR gamma; Peroxisome Proliferator-Activated Receptors; Phenotype; Production; Rattus; Recovery; Recovery of Function; Regulation; Reperfusion Therapy; Role; Signal Transduction; Stroke; System; Testing; base; cytokine; immunoregulation; improved; in vivo; inflammatory marker; injured; macrophage; migration; myelination; nanomolar; nervous system disorder; neurological recovery; neurorestoration; novel; oligodendrocyte precursor; post stroke; precursor cell; promoter; public health relevance; receptor; remyelination; repaired; stroke therapy; tissue repair; transcription factor; white matter; white matter injury

 DESCRIPTION (provided by applicant): White matter (WM) injury, characterized by demyelination and loss of axonal integrity, is an important cause of long-term sensorimotor and cognitive deficits after stroke. A persistent pro-inflammatory microenvironment after stroke is considered one underlying mechanism that hinders oligodendrocyte precursor cell (OPCs) differentiation and maturation into myelinating oligodendrocytes (OLs). Accumulating recent evidence suggests that the different functional phenotypes of microglia/macrophages contribute considerably to the regulation of inflammatory status of injured WM and ultimately impact the WM integrity. Specifically, "alternatively activated" M2 microglia are essential for remyelination and WM repair because they resolve local inflammation, clear broken myelin sheath or cellular debris, and provide trophic factors that promote OPC differentiation. Interleukin-4 (IL-4) is thus far the best characterized inducer for M2 polarization of microglia/macrophages; however, its role in microglia regulation in WM and long term stroke outcomes is not known. We have discovered that IL-4 is a novel endogenous protectant against WM injury and that it promotes WM repair. Our preliminary results show that IL-4 knockout (KO) mice exhibit worse sensorimotor deficits over 14 days after tMCAO. Remarkably, IL-4 KO mice display deteriorated WM injury. Moreover, IL-4 KO mice show markedly reduced numbers of M2 microglia/macrophages in WM-enriched brain regions, including the corpus callosum and striatum after tMCAO. In contrast, intraventricular infusion of IL-4 for 14 days beginning 6h after MCAO attenuates long-term sensorimotor and cognitive deficits and improves WM integrity. In addition to promoting M2 polarization, we have found that IL-4 directly induces the differentiation of primary OPCs into mature OLs at nanomolar concentrations and that this effect of IL-4 on OPCs is mediated through the activation of PPARγ. In this proposal, we will focus on the novel action of IL-4 on WM integrity and explore the underlying mechanisms. We will test the overarching hypothesis that IL-4 promotes WM integrity and long-term neurological recovery after stroke by dual mechanisms, in that it 1) promotes OPC differentiation/maturation via PPARγ activation and 2) potentiates microglia/macrophage polarization toward the beneficial M2 phenotype, which is essential for remyelination and WM repair in demyelinating brains. The Specific Aims to be tested are: Aim 1: Test the hypothesis that post-ischemia IL-4 treatment enhances WM integrity and long-term neurological recovery after stroke. IL-4 will be delivered into the brain by repeated intranasal administrations after reperfusion. The endpoints for assessment include neurological outcomes and various markers for WM integrity. Aim 2: Test the hypothesis that IL-4 induces OPC differentiation into mature OLs and promotes axonal remyelination via PPARγ activation. Aim 3: Test the hypothesis that IL-4 potentiates microglia/macrophage polarization into the inflammation-resolving, tissue repair-enhancing M2 phenotype and restores a "healthy" microenvironment for efficient WM repair.

 描述（由适用提供）：以脱髓鞘和轴突完整性丧失为特征的白质（WM）损伤是中风后长期感觉运动和认知缺陷的重要原因。中风后持续的促炎性微环境被认为是一种潜在的机制，它阻碍了少突胶质细胞前体细胞（OPC）分化和成熟为骨髓的少突胶质细胞（OLS）。累积最近的证据表明，小胶质细胞/巨噬细胞的不同功能表型谨慎地调节受伤的WM的炎症状态，并最终影响WM完整性。具体而言，“替代激活”的M2小胶质细胞对于重新性和WM修复至关重要，因为它们可以解决局部炎症，明显破裂的髓鞘鞘或细胞碎屑，并提供促进OPC分化的营养因子。 远远是小胶质细胞/巨噬细胞M2极化的最佳特征诱导剂；然而，它在WM中的小胶质细胞调节中的作用尚不清楚。我们已经发现IL-4是一种新型的内源性保护剂，以防止WM损伤，并且可以促进WM修复。我们的初步结果表明，在TMCAO后14天内，IL-4敲除（KO）小鼠在14天内暴露了较差的感觉运动缺陷。值得注意的是，IL-4 KO小鼠显示了WM损伤。此外，IL-4 KO小鼠在富含WM的脑区域中显示的M2小胶质细胞/巨噬细胞数量明显减少，包括TMCAO后的call体和纹状体。相比之下，脑室内输注IL-4 14天后6H MCAO减弱了长期的感觉运动，认知可以定义和改善WM完整性。除了促进M2极化外，我们还发现IL-4直接诱导分化 在纳摩尔浓度下，原代OPC成熟的OLS，并且IL-4对OPC的这种影响是通过激活PPARγ介导的。在此提案中，我们将重点关注IL-4对WM完整性的新作用，并探索潜在的机制。 We will test the overarching hypothesis that IL-4 promotes WM integrity and long-term neurological recovery after stroke by dual mechanisms, in that it 1) promotes OPC Differentiation/maturation via PPARγ activation and 2) potentials microglia/macrophage polarization towards the beneficial M2 phenotype, which is essential for remyelination and WM repair in demyelinating brains.要测试的具体目的是：目标1：检验以下假设：疾病后IL-4治疗可增强中风后WM完整性和长期神经恢复。再灌注后，IL-4将通过反复的鼻内施用将IL-4传递到大脑中。评估的终点包括神经系统结局和WM完整性的各种标记。 AIM 2：检验IL-4将OPC分化为成熟OL的假设，并通过PPARγ激活促进轴突再生。 AIM 3：检验IL-4在解散，组织修复增强的M2表型中增强小胶质细胞/巨噬细胞极化的假设，并恢复“健康”的微环境，以有效地修复WM。