IRF5-IRF4 Regulatory Axis: A new Target for Stroke

IRF5-IRF4 调节轴：中风的新目标

• 批准号: 8946680
• 负责人: Fudong Liu
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8946680
• 关键词: Ablation; Acute; Anti-Inflammatory Agents; Anti-inflammatory; Biological; Bone Marrow; Brain; Brain Ischemia; CX3CL1 gene; Cells; Cerebral Ischemia; Chimera organism; Chronic; Coculture Techniques; Data; Dendritic Cells; Down-Regulation; Equilibrium; Figs - dietary; Genes; Goals; IL4 gene; IRF4 gene; Immune; Immune Cell Activation; Immune response; In Vitro; Indium; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interferon Regulatory Factor 1; Interferon Type II; Interferons; Interleukin 4 Receptor; Ischemia; Ischemic Brain Injury; Knock-out; Knockout Mice; Leukocytes; Life; Mediating; Microglia; Middle Cerebral Artery Occlusion; Modeling; Mus; Mutation; Myelogenous; Natural Killer Cells; Neurons; Outcome; Pathway interactions; Patients; Peripheral; Phenotype; Play; Proteins; Regulation; Role; Signal Transduction; Small Interfering RNA; Stroke; Supplementation; Tamoxifen; Testing; Therapeutic; Therapeutic Intervention; Time; Ursidae Family; Virus Diseases; age related; aged; aging brain; disability; macrophage; monocyte; mouse model; neuroprotection; public health relevance; reconstitution; response; tissue repair; toll-like receptor 4

 DESCRIPTION (provided by applicant): Microglial activation is a key element in initiating and perpetuating innate immune responses to cerebral ischemia. Microglial responses are characterized as either M1, classical activation (pro-inflammatory), or M2, alternative activation (anti-inflammatory). The two distinct phenotypes of microglia potentially provide a therapeutic avenue that selectively enhances M2 and/or inhibits M1 activation. The mechanism underlying microglial M1/M2 activation after stroke has not been explored. Studies of peripheral inflammation suggested that interferon regulatory factor 5 (IRF5) and IRF4 are key determinants in mediating macrophage M1/M2 polarization. IRF5 and IRF4 function through TLR4- MyD88-IRF5 and IL4R-Jmjd3-IRF4 pathways to regulate macrophage M1/M2 phenotype respectively. It is suggested that the two pathways act synergistically to mediate M1/M2 polarization. We hypothesize that the IRF5-IRF4 regulatory axis balances the TLR4-MyD88-IRF5 and IL4R-Jmjd3-IRF4 pathways to direct microglial M1/M2 polarization after stroke, and that manipulation of the IRF5-IRF4 regulatory axis confers neuroprotection against ischemia. Inducible conditional knockout (ICKO) and a bone marrow chimera mouse model will be utilized to study the IRF5-IRF4 regulatory axis specifically in microglia or in infiltrating peripheral leukocytes afer stroke. Aim 1 will study the role of the IRF5-IRF4 regulatory axis selectively in microglia after ischemic injury. Using a chronic ICKO model in which IRF5/IRF4 is selectively lost in microglia but intact in peripheral leukocytes, protein over-expression and knockdown, and microglia-neuron co- culture, we will test if manipulation of the IRF5-IRF4 regulatory axis can switch microglial phenotype and reduce ischemic injury after experimental stroke. Aim 2 will investigate whether the IRF5-IRF4 regulatory axis in infiltrating peripheral cells plays an important role in mediating post-ischemic brain injury. Bone marrow chimeras and an acute IRF5/IRF4 ICKO mouse model will be employed. Aim 3 will examine if age-related differences exist in the IRF5-IRF4 regulatory axis after stroke. The IRF5/IRF4 ICKO model will be utilized to examine the IRF5/IRF4 signaling in aged mice. Manipulation of the IRF5- IRF4 regulatory axis in microglia/infiltrating leukocytes may help limit ischemic injury and promote tissue repair after stroke. The study has high translational value and will hopefully identify new biological targets for therapeutic intervention for patients with stroke.

 描述（由适用提供）：小胶质细胞激活是启动和永久性免疫回报与脑缺血的关键要素。小胶质细胞反应的特征是M1，经典激活（促炎）或M2替代激活（抗炎）。小胶质细胞的两种不同表型可能提供了一种治疗途径，可有选择地增强M2和/或抑制M1激活。尚未探索中风后的小胶质细胞M1/m2激活的机制。对周围感染的研究表明，干扰素调节因子5（IRF5）和IRF4是介导巨噬细胞M1/M2极化的关键决定者。 IRF5和IRF4通过TLR4-MYD88-IRF5和IL4R-JMJD3-IRF4途径分别调节巨噬细胞M1/M2表型。建议这两种途径协同介导M1/M2极化。我们假设IRF5-IRF4调节轴平衡了TLR4-MYD88-IRF5和IL4R-JMJD3-IRF4途径在中风后直接直接小胶质细胞M1/M2极化，并且对IRF5-IRF5-IRF4调节轴的操纵进行了操纵。诱导型有条件敲除（ICKO）和骨髓嵌合体模型将用于研究专门针对小胶质细胞或浸润的外围白细胞的IRF5-IRF4调节轴。 AIM 1将在缺血性损伤后选择性地研究IRF5-IRF4调节轴的作用。使用慢性ICKO模型，其中IRF5/IRF4在小胶质细胞中有选择性丢失，但在外周血白细胞，蛋白质过表达和敲低以及小胶质细胞 - 神经元共培养中完整，我们将测试是否操纵IRF5-IRF4调节型irf5-irf4调节型可以切换小胶质细胞型和降低小压缩性。 AIM 2将研究浸润外周细胞中的IRF5-IRF4调节轴是否在介导缺血后脑损伤中起重要作用。将雇用骨髓嵌合体和急性IRF5/IRF4 ICKO小鼠模型。 AIM 3将检查中风后IRF5-IRF4调节轴中与年龄相关的差异。 IRF5/IRF4 ICKO模型将用于检查老年小鼠中的IRF5/IRF4信号传导。在小胶质细胞/浸润白细胞中对IRF5-IRF4调节轴操纵可能有助于限制缺血性损伤并促进中风后的组织修复。这项研究具有很高的翻译价值，并有望确定中风患者治疗干预的新生物学靶标。