Immunomodulation of white matter integrity after stroke

中风后白质完整性的免疫调节

基本信息

批准号：
9659384
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
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9659384
关键词：
Anti-Inflammatory Agents 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 Injections 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 Mus Myelin Basic Proteins Myelin Sheath Neuroglia Neurologic Deficit Neurological outcome Neurons Oligodendroglia 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 conditional knockout cytokine immunoregulation improved in vivo inflammatory marker 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 model stroke outcome stroke therapy tissue repair transcription factor white matter white matter injury

项目摘要

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（由申请人提供）：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，中风后持续的促炎症微环境被认为是潜在的原因之一。阻碍少突胶质细胞前体细胞（OPC）分化和成熟为髓鞘少突胶质细胞（OL）的机制最近积累的证据表明，少突胶质细胞的不同功能表型。小胶质细胞/巨噬细胞对调节受损 WM 的炎症状态有很大贡献，并最终影响 WM 的完整性。具体来说，“交替激活”的 M2 小胶质细胞对于髓鞘再生和 WM 修复至关重要，因为它们可以解决局部炎症、清除破损的髓鞘或细胞碎片。并提供促进 OPC 分化的营养因子。迄今为止，IL-4 是小胶质细胞/巨噬细胞 M2 极化的最佳特征诱导剂；然而，其在 WM 和长期中风结局中小胶质细胞调节中的作用尚不清楚，我们发现 IL-4 是一种针对 WM 损伤的新型内源性保护剂，并且它可以促进 WM 损伤。 WM 修复。我们的初步结果表明，IL-4 敲除 (KO) 小鼠在 tMCAO 后 14 天表现出更严重的感觉运动缺陷。值得注意的是，IL-4 KO 小鼠表现出 WM 损伤恶化。此外，在 tMCAO 后，IL-4 KO 小鼠在富含 WM 的大脑区域（包括胼胝体和纹状体）中表现出 M2 小胶质细胞/巨噬细胞数量显着减少，相比之下，从 6 小时后开始脑室内输注 IL-4 14 天。 MCAO 减轻长期感觉运动和认知缺陷并改善 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。 IL-4 在纳摩尔浓度下将初级 OPC 转化为成熟的 OL，并且 IL-4 对 OPC 的这种作用是通过 PPARγ 的激活介导的。在本提案中，我们将重点关注 IL-4 对 WM 完整性的新作用并探索其潜在机制。我们将检验这一总体假设，即 IL-4 通过双重机制促进 WM 完整性和中风后长期神经功能恢复，因为它 1) 通过 PPARγ 激活促进 OPC 分化/成熟，2)增强小胶质细胞/巨噬细胞向有益的 M2 表型极化，这对于脱髓鞘大脑中的髓鞘再生和 WM 修复至关重要。要测试的具体目标是：目标 1：检验缺血后 IL-4 治疗增强 WM 完整性和长寿命的假设。中风后的长期神经功能恢复。再灌注后通过重复鼻内给药将 IL-4 输送到大脑中。评估终点包括神经功能结果和 WM 的各种标志物。目标 2：检验 IL-4 诱导 OPC 分化为成熟 OL 并通过 PPARγ 激活促进轴突髓鞘再生的假设。目标 3：检验 IL-4 增强小胶质细胞/巨噬细胞极化以解决炎症和组织修复的假设。增强 M2 表型并恢复“健康”的微环境，以实现有效的 WM 修复。