Circadian Control of Brain-peripheral Immune Response After Stroke

卒中后脑外周免疫反应的昼夜节律控制 衰老和昼夜节律是免疫系统的强大调节器，免疫系统 反应是卒中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， 我们将重点研究脑到颈部的淋巴结信号通路(Esposito等人，NAT Commun 2019年)。因为淋巴引流是由昼夜节律调节的，而昼夜节律 在衰老过程中，我们假设这一途径可能提供了一种新的整合机制 它连接了中风病理生理学中的三个主要因素：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和自然2020上)表明 (I)昼夜节律显著影响脑缺血后损伤的进展；(Ii) BMal1在脑内的表达和HO1在星形胶质细胞中的表达在活动期高于非活动期 卒中活动期较高的脑HO1流入CLN可能减少氧化作用 CLN淋巴管内皮细胞应激性4-羟基壬烯醛(4HNE)；(Iv)脑内HO1引流增加 卒中活动期转化为CLN可降低脾组织中细胞毒CD8 T细胞(TLR4)；(V)CD8 卒中活动期T细胞浸润和脑内皮细胞CxCl10、HMGB1可能降低； (Vi)脑脊液向CLN的流出受昼夜节律和年龄的影响；。(Vii)年龄。 在活动期卒中改变HO1脑到CLN的引流。 我们将检验这一总体假设：卒中活动期星形细胞HO1(ZT13)放大 慢性肾炎的内源性抗氧化应激反应，减轻脾炎症，并减少 脑内皮细胞炎症，而衰老改变了昼夜节律基因和HO1排泄 中枢神经系统，从而削弱了活动期中风的这种内源性保护性反应。 在目标1，我们将剖析脑-颈淋巴结局灶性损伤后的昼夜节律效应。 缺血症。在目标2中，我们将研究昼夜节律对中风后大脑的影响。 内皮细胞发炎。在目标3中，我们将研究衰老对昼夜节律的影响- 局灶性脑缺血后介导的全身反应。此项目应定义新的 将中风免疫反应与昼夜生物学和衰老联系起来的机制，因此 为寻找昼夜靶标和生物标志物提供了一个新的概念框架- 老年患者的时间卒中。

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.