Interleukin-33 as an immune therapy for stroke

Interleukin-33 作为中风免疫疗法

• 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
• 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

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的主要医疗问题之一。以经典的神经为中心 中风研究中大脑的观点可能阻碍了有效疗法的发展。白质 （WM）受伤，其特征是髓磷脂和产生髓磷脂的少突胶质细胞（OLS）是主要原因 中风后的功能障碍，但直到最近才被广泛理解。能够 需要减轻灰质和WM病理生理学，以实现全面的脑部保护和长期 神经恢复。积累的证据表明，小胶质细胞的不同功能表型 巨噬细胞对受伤大脑的炎症状态的调节产生了很大贡献 影响大脑完整性。具体而言，M2样表型对于组织保存和脑修复至关重要 因为M2细胞可以解决局部炎症，清除细胞碎屑并提供保护因子。 白介素-33（IL-33）是一种多功能细胞因子，涉及广泛的免疫反应， 包括增强巨噬细胞中的M2样反应。有趣的是，IL-33及其受体都 由CNS表示由ST2和IL-1受体辅助蛋白组成。 IL-33/ST2的精确作用 然而，缺血性大脑中的信号传导并不是很好的特征和基本的作用机理 仍然未知。我们的初步结果表明，ST2敲除（KO）小鼠表现出大脑梗塞扩大， 瞬时脑动脉闭塞（TMCAO）后，WM损伤恶化和较差的感觉运动缺陷。 相反，TMCAO后IL-33 1H的鼻内输注减弱了脑梗塞。值得注意的是，ST2 KO小鼠 显示出M2样标记的表达降低和缺血中M1样标记的表达增加 脑。我们在体外发现IL-33增强了M2极化，尤其是IL-10的产生 小胶质细胞。此外，IL-33治疗增强了针对氧气剥夺的神经元和OL存活 （OGD）在神经元 - 胶质混合培养物中，可以通过中和抗体消除。 该提案将进一步探讨IL-33/ST2信号传导在缺血性脑损伤之后的保护作用 希望将IL-33开发为一种新颖的，临床上可行的治疗策略，以改善中风后大脑 损害。我们将测试总体假设，即IL-33/ST2信号的激活可预防 通过增强小胶质细胞/巨噬细胞极化向保护性M2表型，脑缺血通过它 进而限制了中风后神经元和WM损伤。要测试的具体目的是：目标1：测试 IL-33治疗后的假设可以预防年轻小鼠和老年小鼠的局灶性脑缺血。目的 2：测试IL-33/ST2信号传导通过移动来缓解缺血性神经元和OL损伤的假设 小胶质细胞朝向保护表型。目标3：检验IL-10是基本保护因素的假设 由IL-33处理的小胶质细胞发布。这项研究的成功将阐明IL-33作为潜在的治疗 灰质和WM保护和中风后的长期恢复的策略。