Interleukin-33 as an immune therapy for stroke

Interleukin-33 作为中风免疫疗法

基本信息

批准号：
10045942
负责人：
Xiaoming Hu
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-10-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10045942
关键词：
3-Dimensional Acute Adult Aftercare Attenuated Automobile Driving Brain Brain Diseases Brain Infarction Brain Injuries Cells Cerebral Ischemia Cessation of life Clear Cell Clinical Coculture Techniques Data Development Dichloromethylene Diphosphonate Disease Dose Exhibits Functional disorder Future Glucose Immune Immune response Immunotherapy Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Infusion procedures Injury Interleukin Activation Interleukin-1 Receptors Interleukin-10 Interleukins Intranasal Administration Ischemia Ischemic Brain Injury Ischemic Stroke Knockout Mice Light Medical Methods Microglia Middle Cerebral Artery Occlusion Mus Myelin Nervous System Physiology Neuroglia Neurologic Neurologic Deficit Neurological outcome Neurons Nose Nuclear Oligodendroglia Oxygen Pathology Phenotype Play Production Proteins Recovery Regulation Reperfusion Therapy Research Role Signal Pathway Signal Transduction Spinal cord injury Stroke Survivors Testing Therapeutic Therapeutic Studies Tissue Preservation United States Veterans aged brain repair cell injury cytokine deprivation disability effective therapy functional disability functional outcomes gray matter immunoregulation improved in vivo macrophage military veteran nervous system disorder neurological recovery neuron loss neutralizing antibody novel novel therapeutics post stroke preservation protective effect protective factors receptor release factor response stroke model stroke therapy success white matter white matter injury

项目摘要

Stroke is one of the major medical concerns for United States military veterans. The classically neurocentric view of the brain in stroke research may have hindered the development of effective therapies. White matter (WM) injury, characterized by loss of myelin and myelin-producing oligodendrocytes (OLs), is a major cause of functional disability after stroke but has not been widely appreciated until recently. Strategies that are able to alleviate both gray matter and WM pathophysiology are needed to achieve full brain protection and long-term neurological recovery. Accumulating evidence suggests that the different functional phenotypes of microglia/ macrophages contribute considerably to the regulation of inflammatory status of injured brain and ultimately impact the brain integrity. Specifically, M2-like phenotype is essential for tissue preservation and brain repair because M2 cells resolve local inflammation, clear cell debris, and provide protective factors. Interleukin-33 (IL-33) is a multifunctional cytokine that involves in a wide range of immune responses, including potentiating M2-like responses in macrophages. Interestingly, both IL-33 and its receptor, which consists of ST2 and IL-1 receptor accessory protein, are expressed in the CNS. The precise roles of IL-33/ST2 signaling in the ischemic brain, however, are not well-characterized and the underlying mechanisms of action remain unknown. Our preliminary results show that ST2 knockout (KO) mice exhibited enlarged brain infarct, deteriorated WM injury and worse sensorimotor deficits after transient middle cerebral artery occlusion (tMCAO). In contrast, intranasal infusion of IL-33 1h after tMCAO attenuates brain infarct. Remarkably, ST2 KO mice showed reduced expression of M2-like markers and increased expression of M1-like markers in the ischemic brain. We have found in vitro that IL-33 potentiates M2 polarization, especially IL-10 production in primary microglia. Furthermore, IL-33 treatment enhanced neuronal and OL survival against oxygen glucose deprivation (OGD) in neuron-glia mixed culture, which can be abolished by IL-10 neutralizing antibody. This proposal will further explore the protective effect of IL-33/ST2 signaling after ischemic brain injury with the hope of developing IL-33 into a novel, clinically feasible therapeutic strategy to ameliorate post-stroke brain damage. We will test the overarching hypothesis that the activation of IL-33/ST2 signaling protects against cerebral ischemia by enhancing microglia/macrophage polarization toward a protective M2 phenotype, which in turn restricting neuronal and WM injury after stroke. The Specific Aims to be tested are: Aim 1: Test the hypothesis that IL-33 post-treatment protects against focal cerebral ischemia in both young and aged mice. Aim 2: Test the hypothesis that IL-33/ST2 signaling ameliorates ischemic neuronal and OL damage via shifting microglia toward a protective phenotype. Aim 3: Test the hypothesis that IL-10 is an essential protective factor released by IL-33-treated microglia. The success of this study will shed light on IL-33 as a potential therapeutic strategy for both gray matter and WM protection and long-term recovery after stroke.

中风是美国退伍军人面临的主要医疗问题之一。经典的神经中心论中风研究中的大脑观点可能阻碍了有效疗法的开发。白质 (WM) 损伤，以髓磷脂和产生髓磷脂的少突胶质细胞 (OL) 损失为特征，是导致中风后的功能障碍，但直到最近才得到广泛认识。能够采取的策略需要减轻灰质和 WM 病理生理学，以实现全面的大脑保护和长期神经功能恢复。越来越多的证据表明小胶质细胞/的不同功能表型巨噬细胞对调节受伤大脑的炎症状态有很大贡献，并最终影响大脑完整性。具体来说，M2 样表型对于组织保存和大脑修复至关重要因为M2细胞可以解决局部炎症、清除细胞碎片并提供保护因子。白介素 33 (IL-33) 是一种多功能细胞因子，参与广泛的免疫反应，包括增强巨噬细胞中的 M2 样反应。有趣的是，IL-33 及其受体，由 ST2 和 IL-1 受体辅助蛋白组成，在 CNS 中表达。 IL-33/ST2的确切作用然而，缺血性大脑中的信号传导尚未得到很好的表征，并且其潜在的作用机制仍然未知。我们的初步结果表明 ST2 敲除（KO）小鼠表现出扩大的脑梗塞，短暂性大脑中动脉闭塞（tMCAO）后 WM 损伤恶化，感觉运动缺陷恶化。相反，tMCAO 后 1 小时鼻内输注 IL-33 可减轻脑梗塞。值得注意的是，ST2 KO 小鼠缺血组中 M2 样标记物的表达减少，M1 样标记物的表达增加脑。我们在体外发现 IL-33 增强 M2 极化，尤其是原代细胞中 IL-10 的产生小胶质细胞。此外，IL-33 治疗可增强神经元和 OL 在氧糖剥夺条件下的存活率 (OGD)在神经元-胶质细胞混合培养物中，可被IL-10中和抗体消除。本提案将进一步探讨IL-33/ST2信号在缺血性脑损伤后的保护作用希望将 IL-33 开发成一种临床可行的新型治疗策略，以改善中风后大脑损害。我们将测试一个总体假设，即 IL-33/ST2 信号传导的激活可以防止通过增强小胶质细胞/巨噬细胞向保护性 M2 表型极化来治疗脑缺血，进而限制中风后神经元和 WM 损伤。要测试的具体目标是：目标 1：测试假设 IL-33 治疗后可以预防年轻和老年小鼠的局灶性脑缺血。目的 2：检验 IL-33/ST2 信号传导通过转移改善缺血性神经元和 OL 损伤的假设小胶质细胞向保护性表型发展。目标 3：检验 IL-10 是重要保护因子的假设由 IL-33 处理的小胶质细胞释放。这项研究的成功将揭示 IL-33 作为一种潜在的治疗方法灰质和 WM 保护以及中风后长期恢复的策略。