Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN, United States.
Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Fort Wayne, IN, United States.
Front Immunol. 2023 Mar 31;14:1148069. doi: 10.3389/fimmu.2023.1148069. eCollection 2023.
Tissue plasminogen activator (tPA) is the only FDA-approved drug for the treatment of ischemic stroke. Delayed tPA administration is associated with increased risks of blood-brain barrier (BBB) disruption and hemorrhagic transformation. Studies have shown that interferon beta (IFNβ) or type I IFN receptor (IFNAR1) signaling confers protection against ischemic stroke in preclinical models. In addition, we have previously demonstrated that IFNβ can be co-administered with tPA to alleviate delayed tPA-induced adverse effects in ischemic stroke. In this study, we investigated the time limit of IFNβ treatment on the extension of tPA therapeutic window and assessed the effect of IFNβ on modulating microglia (MG) phenotypes in ischemic stroke with delayed tPA treatment. Mice were subjected to 40 minutes transient middle cerebral artery occlusion (MCAO) followed by delayed tPA treatment in the presence or absence of IFNβ at 3h, 4.5h or 6h post-reperfusion. In addition, mice with MG-specific IFNAR1 knockdown were generated to validate the effects of IFNβ on modulating MG phenotypes, ameliorating brain injury, and lessening BBB disruption in delayed tPA-treated MCAO mice. Our results showed that IFNβ extended tPA therapeutic window to 4.5h post-reperfusion in MCAO mice, and that was accompanied with attenuated brain injury and lessened BBB disruption. Mechanistically, our findings revealed that IFNβ modulated MG polarization, leading to the suppression of inflammatory MG and the promotion of anti-inflammatory MG, in delayed tPA-treated MCAO mice. Notably, these effects were abolished in MG-specific IFNAR1 knockdown MCAO mice. Furthermore, the protective effect of IFNβ on the amelioration of delayed tPA-exacerbated ischemic brain injury was also abolished in these mice. Finally, we identified that IFNβ-mediated modulation of MG phenotypes played a role in maintaining BBB integrity, because the knockdown of IFNAR1 in MG partly reversed the protective effect of IFNβ on lessening BBB disruption in delayed tPA-treated MCAO mice. In summary, our study reveals a novel function of IFNβ in modulating MG phenotypes, and that may subsequently confer protection against delayed tPA-exacerbated brain injury in ischemic stroke.
组织型纤溶酶原激活物（tPA）是唯一经 FDA 批准用于治疗缺血性中风的药物。tPA 给药延迟与血脑屏障（BBB）破坏和出血性转化的风险增加有关。研究表明，干扰素β（IFNβ）或 I 型干扰素受体（IFNAR1）信号转导可在临床前模型中为缺血性中风提供保护。此外，我们之前已经证明，IFNβ可以与 tPA 联合给药，以减轻缺血性中风中延迟 tPA 诱导的不良反应。在这项研究中，我们研究了 IFNβ 治疗的时间限制对 tPA 治疗窗口的扩展，并评估了 IFNβ 对调节延迟 tPA 治疗的缺血性中风中小胶质细胞（MG）表型的影响。在再灌注后 3h、4.5h 或 6h 时，在存在或不存在 IFNβ 的情况下，将小鼠进行 40 分钟短暂性大脑中动脉闭塞（MCAO），然后进行延迟 tPA 治疗。此外，生成了 MG 特异性 IFNAR1 敲低的小鼠，以验证 IFNβ 对调节 MG 表型、减轻脑损伤和减少延迟 tPA 治疗的 MCAO 小鼠 BBB 破坏的影响。我们的结果表明，IFNβ 将 tPA 的治疗窗口扩展到 MCAO 小鼠再灌注后 4.5h，同时伴有脑损伤减轻和 BBB 破坏减少。从机制上讲，我们的发现表明，IFNβ 调节 MG 极化，导致抑制炎症性 MG 并促进抗炎性 MG，在延迟 tPA 治疗的 MCAO 小鼠中。值得注意的是，在 MG 特异性 IFNAR1 敲低的 MCAO 小鼠中，这些作用被消除。此外，在这些小鼠中，IFNβ 对改善延迟 tPA 加重的缺血性脑损伤的保护作用也被消除。最后，我们确定 IFNβ 介导的 MG 表型调节在维持 BBB 完整性方面发挥作用，因为 MG 中的 IFNAR1 敲低部分逆转了 IFNβ 对延迟 tPA 治疗的 MCAO 小鼠 BBB 破坏减少的保护作用。总之，我们的研究揭示了 IFNβ 调节 MG 表型的新功能，这可能随后为缺血性中风中延迟 tPA 加重的脑损伤提供保护。
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