Interferon beta modulates neuroinflammation and extends tPA therapeutic window in ischemic stroke

干扰素β调节神经炎症并延长缺血性中风的 tPA 治疗窗

• 批准号: 10391442
• 负责人: JUI-HUNG JIMMY YEN
• 金额: $ 34.45万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2024-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391442
• 关键词: Acute; Adverse effects; Alteplase; Animal Model; Animal Testing; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Bone Marrow; Brain; Brain Infarction; Brain Injuries; Cause of Death; Cells; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Chimera organism; Complication; Encephalitis; Exhibits; FDA approved; Genetic; Hemorrhage; IFNAR1 gene; Immune; In Vitro; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Interferon-beta; Intervention; Investigation; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Lead; Link; MMP3 gene; MMP9 gene; Mediating; Medical; Microglia; Middle Cerebral Artery Occlusion; Multiple Sclerosis; Mus; Neurologic Deficit; Onset of illness; Pathway interactions; Patients; Peripheral; Phase; Platelet-Derived Growth Factor alpha Receptor; Pre-Clinical Model; Production; Prognosis; Property; Relapsing-Remitting Multiple Sclerosis; Reperfusion Therapy; Risk; Rodent; Signal Pathway; Signal Transduction; Stroke; Survivors; Testing; Therapeutic; Tumor-infiltrating immune cells; United States; blood-brain barrier disruption; cytokine; disability; effective therapy; immune activation; immunoregulation; in vivo; mRNA Expression; multiple sclerosis treatment; neuroinflammation; neuroprotection; novel strategies; novel therapeutics; peripheral blood; platelet-derived growth factor C; pre-clinical; protective effect; stroke model; stroke outcome; stroke patient; stroke recovery; translational therapeutics; type I interferon receptor

PROJECT SUMMARY Stroke is a leading cause of death and results in permanent disability in up to 30% of survivors. Among them, ischemic stroke accounts for about 87 percent of all cases. Tissue plasminogen activator (tPA) is the only effective treatment for ischemic stroke but has a very limited therapeutic window of 3-4.5h. Undesirably, delayed tPA treatment beyond 3-4.5h disease onset increases risk of blood brain barrier (BBB) disruption and hemorrhagic transformation (HT) that further exacerbates brain injury. In addition, tPA has been shown to aggravate neuroinflammation by enhancing microglia (MG) activation. Thus, there is a critical need to develop a therapeutic approach to attenuate brain inflammation and widen the tPA therapeutic window following ischemic stroke. Interferon beta (IFNβ), a cytokine with immunomodulatory properties, was approved by the FDA for the treatment of relapsing-remitting multiple sclerosis (MS) for more than a decade. It has been well-established that IFNβ suppresses CNS inflammation in MS, thereby suggesting that IFNβ might have a therapeutic potential for the treatment of ischemic stroke. Indeed, our recent findings showed that IFNβ attenuated ischemia-induced brain infarct and lessened neurological deficits in rodent stroke models, thereby demonstrating that IFNβ confers a protective effect against ischemic stroke. However, detailed mechanisms involved in the protective effects of IFNβ on the suppression of ischemia-induced primary and reperfusion-mediated secondary neuroinflammation remain to be elucidated. More importantly, the effect of IFNβ on tPA-mediated neuroinflammation and delayed tPA-induced BBB disruption and HT in the ischemic brain is unknown. We hypothesize that IFNβ ameliorate ischemic brain injury by converting ischemia, reperfusion, and tPA-induced inflammatory MG into anti- inflammatory MG and modulating inflammatory immune cell infiltration. In addition, IFNβ extends the tPA therapeutic window by inhibiting delayed tPA-induced MMP3/9 production, BBB disruption, and HT in the ischemic brain. We propose the following three specific aims to test our hypothesis. In Aim 1, we will test the effect of IFNβ, co-administered with tPA, on ischemic brain injury and on the tPA therapeutic window in ischemic stroke. In Aim 2, we will determine the effect of IFNβ, co-administered with tPA, on MG activation during acute phase and on infiltrating inflammatory immune cell activation during sub-acute phase in ischemic stroke. In Aim 3, we will determine whether IFNβ alleviates delayed tPA-induced BBB disruption and HT in ischemic stroke. The completion of our proposed studies will provide strong evidence that IFNβ can be developed as a novel therapy for ischemic stroke and ultimately lead to a new venue of medical intervention for cerebral ischemia.

项目摘要 中风是死亡的主要原因，并导致高达30%的幸存者永久性残疾。其中， 缺血性中风约占所有病例的87%。组织型纤溶酶原激活剂（tPA）是唯一的 有效治疗缺血性卒中，但治疗窗非常有限，仅为3- 4.5小时。不希望的，延迟的 tPA治疗超过疾病发作3- 4.5小时会增加血脑屏障（BBB）破坏的风险， 出血性转化（HT），进一步加重脑损伤。此外，tPA已被证明 通过增强小胶质细胞（MG）活化来加重神经炎症。因此，迫切需要制定一个 减轻脑炎症和拓宽缺血后tPA治疗窗的治疗方法 中风干扰素β（IFNβ）是一种具有免疫调节特性的细胞因子，已被FDA批准用于治疗 治疗复发缓解型多发性硬化症（MS）超过十年。众所周知， IFNβ抑制MS的CNS炎症，从而表明IFNβ可能具有治疗MS的潜力。 缺血性中风的治疗事实上，我们最近的研究结果表明，IFNβ减弱了缺血诱导的 脑梗死和减少神经功能缺损，从而证明IFNβ赋予 对缺血性中风有保护作用。然而，涉及保护作用的详细机制， 干扰素β抑制缺血诱导的原发性和再灌注介导的继发性神经炎症 仍有待阐明。更重要的是，IFNβ对tPA介导的神经炎症的作用和延迟 缺血性脑中tPA诱导的BBB破坏和HT尚不清楚。我们假设IFNβ改善了 通过将缺血、再灌注和tPA诱导的炎性MG转化为抗- 炎性MG和调节炎性免疫细胞浸润。此外，IFNβ延长了tPA 通过抑制延迟tPA诱导的MMP 3/9产生，BBB破坏和HT的治疗窗口， 脑缺血我们提出以下三个具体目标来检验我们的假设。在目标1中，我们将测试 IFNβ与tPA联合给药对缺血性脑损伤和缺血性脑损伤中tPA治疗窗的影响 中风在目的2中，我们将确定IFNβ与tPA联合给药对急性期MG活化的影响。 期和亚急性期浸润性炎症免疫细胞活化的影响。在Aim中 3、我们将确定IFNβ是否能延迟缺血性卒中中tPA诱导的BBB破坏和HT。 我们拟议研究的完成将提供强有力的证据表明IFNβ可以开发为一种新型药物 治疗缺血性中风，并最终导致脑缺血的医学干预的新途径。

项目成果

Isolation of Mouse Cerebral Microvasculature for Molecular and Single-Cell Analysis.

分离小鼠大脑微脉管系统进行分子和单细胞分析。

• DOI: 10.3389/fncel.2020.00084
• 发表时间: 2020
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Paraiso,HallelC;Wang,Xueqian;Kuo,Ping-Chang;Furnas,Destin;Scofield,BarbaraA;Chang,Fen-Lei;Yen,Jui-Hung;Yu,I-Chen
• 通讯作者: Yu,I-Chen

4-Ethylguaiacol Modulates Neuroinflammation and Promotes Heme Oxygenase-1 Expression to Ameliorate Brain Injury in Ischemic Stroke.

• DOI: 10.3389/fimmu.2022.887000
• 发表时间: 2022
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Weng, Wen-Tsan;Kuo, Ping-Chang;Scofield, Barbara A.;Paraiso, Hallel C.;Brown, Dennis A.;Yu, I-Chen;Yen, Jui-Hung
• 通讯作者: Yen, Jui-Hung

Immunoresponsive gene 1 modulates the severity of brain injury in cerebral ischaemia.

• DOI: 10.1093/braincomms/fcab187
• 发表时间: 2021
• 期刊: Brain communications
• 影响因子: 4.8
• 作者: Kuo PC;Weng WT;Scofield BA;Furnas D;Paraiso HC;Yu IC;Yen JH
• 通讯作者: Yen JH

4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis.

4-乙基鸟醇调节神经炎症和Th1/Th17在实验性自身免疫性脑脊髓炎中改善疾病严重程度的分化。

• DOI: 10.1186/s12974-021-02143-w
• 发表时间: 2021-05-11
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Weng WT;Kuo PC;Brown DA;Scofield BA;Furnas D;Paraiso HC;Wang PY;Yu IC;Yen JH
• 通讯作者: Yen JH

Interferon-β modulates microglial polarization to ameliorate delayed tPA-exacerbated brain injury in ischemic stroke.

干扰素-β调节小胶质极化，以改善缺血性中风中TPA诊断的脑损伤。

• DOI: 10.3389/fimmu.2023.1148069
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3