Circadian Control of Brain-peripheral Immune Response After Stroke

中风后大脑周围免疫反应的昼夜节律控制

• 批准号: 10733910
• 负责人: Elga Esposito
• 金额: $ 47.52万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733910
• 关键词: 4 hydroxynonenal; ARNTL gene; Address; Affect; Age; Aging; Astrocytes; Attenuated; B-Lymphocytes; Biological Markers; Blood; Brain; Brain Injuries; C57BL/6 Mouse; CD8-Positive T-Lymphocytes; CXCL10 gene; CXCR3 gene; Carnosine; Cell Separation; Cells; Cerebral Ischemia; Cerebrospinal Fluid; Cervical lymph node group; Circadian Rhythms; Coculture Techniques; Data; Disease; Drainage procedure; Endothelium; Etiology; Female; Flow Cytometry; Functional disorder; Genes; Glucose; HMGB1 gene; Hypericin; Immune; Immune response; Immune system; Immunity; Immunomodulators; In Vitro; Infarction; Inflammation; Injury; Ischemic Brain Injury; Knockout Mice; Lymph Node Dissections; Lymph Node Drainage; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Endothelium; Macrophage; Mediating; Microglia; Modeling; Mus; Nature; Oxidative Stress; Oxygen; Pathway interactions; Patients; Peripheral; Phase; Plasma; Primary Cell Cultures; Publishing; Recombinants; Rodent; Signal Pathway; Signal Transduction; Sleep; Small Interfering RNA; Spleen; Standardization; Stroke; T cell infiltration; T-Lymphocyte; TLR4 gene; Testing; Time; Validation; Work; age effect; aged; awake; behavioral outcome; biological adaptation to stress; brain cell; brain endothelial cell; circadian; circadian biology; circadian regulation; cytokine; cytotoxic CD8 T cells; deprivation; gain of function; heme oxygenase-1; in vivo; loss of function; lymph nodes; lymphatic drainage; male; mind control; neuroinflammation; novel; post stroke; potential biomarker; response; spatiotemporal; stroke model; targeted biomarker

Circadian control of brain-peripheral immune response after stroke Aging and circadian rhythm are strong modulators of the immune system, and the immune response is a major contributor to stroke pathophysiology. But how aging and circadian rhythm interacts to influence immune response after stroke remains poorly understood. In this project, we will focus on the brain-to-cervical lymph node signaling pathway (Esposito et al, Nat Commun 2019). Because lymphatic drainage is regulated by circadian rhythm, and circadian rhythm is altered in aging, we hypothesize that this pathway may provide a novel integrating mechanism that connects these 3 major factors in stroke pathophysiology: immune response, circadian phase, and aging. Pilot data (some published in Esposito et al, Nat Commun 2019 and Nature 2020) suggest that (i) circadian phase significantly influences the progression of injury after cerebral ischemia; (ii) Bmal1 expression in brain and HO1 in astrocytes are higher after active phase vs inactive phase strokes; (iii) higher brain HO1 draining into CLN in active phase stroke may decrease oxidative stress 4-Hydroxynonenal (4HNE) in CLN lymphatic endothelium; (iv) higher brain HO1 draining into CLN in active phase stroke may reduce cytotoxic CD8+ T cells (TLR4+) in spleen; (v) CD8+ T cell infiltration and brain endothelial Cxcl10 and Hmgb1 may be lower in active phase stroke; (vi) CSF drainage from brain to CLN is affected by both circadian phase and aging; (vii) aging alters HO1 brain-to-CLN drainage in active phase stroke. We will test this overall hypothesis: Astrocytic HO1 in active phase stroke (ZT13) amplifies endogenous anti-oxidative stress response in CLN, reduces splenic inflammation, and decreases brain endothelial inflammation, whereas aging alters circadian genes and HO1 drainage in the CNS, thus weakening this endogenous protective response in active phase stroke. In Aim 1, we will dissect circadian effects in brain-cervical lymph node signaling after focal cerebral ischemia. In Aim 2, we will investigate the effects of circadian rhythm in post-stroke brain endothelial inflammation. In Aim 3, we will investigate effects of aging in circadian rhythm- mediated systemic response after focal cerebral ischemia. This project should define new mechanisms that connect the stroke immune response with circadian biology and aging, thus provide a new conceptual framework for seeking targets and biomarkers for day-time vs night- time strokes in aging patients.

脑卒中后脑-外周免疫反应的昼夜节律调控 衰老和昼夜节律是免疫系统的强调节剂，并且免疫系统 反应是中风病理生理学的主要因素。但衰老和昼夜节律 相互作用影响中风后的免疫反应仍然知之甚少。在这个项目中， 我们将集中于脑-颈淋巴结信号通路（Esposito等，Nat Commun 2019年）。因为淋巴引流受昼夜节律调节，而昼夜节律是 随着年龄的增长，我们推测这条通路可能提供了一种新的整合机制， 在中风的病理生理学中，这三个主要因素相互关联：免疫反应，昼夜节律， 阶段和老化。 试点数据（一些发表在Esposito等人，Nat Commun 2019和Nature 2020中）表明， (i)昼夜节律显著影响脑缺血后损伤的进展;（ii） 脑组织中Bmal 1和星形胶质细胞中HO 1的表达在活动期后高于非活动期 中风;（iii）在活动期中风中流入CLN的较高脑HO 1可能会降低氧化应激水平。 CLN淋巴管内皮中应激4-羟基壬烯醛（4 HNE）;（iv）较高脑HO 1引流 在活动期中风中进入CLN可以减少脾脏中的细胞毒性CD 8 + T细胞（TLR 4+）;（v）CD 8 + T细胞（TLR 4+） 脑卒中活动期T细胞浸润和脑内皮细胞Cxcl 10、Hmgb 1可能较低; (vi)从脑到CLN的CSF引流受昼夜节律和衰老的影响;（vii）衰老 在活动期卒中中改变HO 1脑至CLN的引流。 我们将测试这一总体假设：活跃期卒中（ZT 13）中的星形胶质细胞HO 1放大 CLN中的内源性抗氧化应激反应，减少脾脏炎症， 脑内皮炎症，而老化改变昼夜节律基因和HO 1排水在脑 中枢神经系统，从而削弱这种内源性保护反应在活跃期中风。 在目标1中，我们将剖析局灶性脑缺血后脑-颈淋巴结信号传导的昼夜节律效应， 缺血在目标2中，我们将研究中风后大脑昼夜节律的影响 内皮炎症在目标3中，我们将研究衰老对昼夜节律的影响- 介导局灶性脑缺血后的全身反应。这个项目应该定义新的 将中风免疫反应与昼夜节律生物学和衰老联系起来的机制， 提供了一个新的概念框架，用于寻找白天与夜间的目标和生物标志物- 老年患者的中风时间。