Interferon-β modulates microglial polarization to ameliorate delayed tPA-exacerbated brain injury in ischemic stroke.
Interferon-β modulates microglial polarization to ameliorate delayed tPA-exacerbated brain injury in ischemic stroke.
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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
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
组织纤溶酶原激活剂（tPA）是FDA批准的唯一用于治疗缺血性卒中的药物。延迟tPA给药与血脑屏障（BBB）破坏和出血性转化的风险增加相关。研究表明，干扰素β（IFNβ）或I型IFN受体（IFNAR1）信号传导在临床前模型中可保护患者免受缺血性卒中的影响。此外，我们之前已经证明IFNβ可以与tPA联合给药，以减轻缺血性卒中中迟发性tPA诱导的不良反应。在这项研究中，我们研究了IFNβ治疗延长tPA治疗窗的时间限制，并评估了IFNβ对延迟tPA治疗的缺血性卒中中小胶质细胞（MG）表型的调节作用。将小鼠进行短暂的大脑中动脉闭塞（MCAO）40分钟，然后在再灌注后3小时、4.5小时或6小时在存在或不存在IFNβ的情况下延迟tPA治疗。此外，产生MG特异性IFNAR1敲低的小鼠以验证IFNβ对调节MG表型、改善脑损伤和减轻延迟tPA处理的MCAO小鼠中的BBB破坏的作用。结果表明，IFNβ可延长tPA治疗窗至再灌注后4.5h，并可减轻脑损伤和血脑屏障破坏。从机制上讲，我们的研究结果表明，IFNβ调节MG极化，导致延迟tPA治疗的MCAO小鼠中炎性MG的抑制和抗炎MG的促进。值得注意的是，这些作用在MG特异性IFNAR1敲低的MCAO小鼠中被消除。此外，IFNβ对这些小鼠中延迟tPA加重的缺血性脑损伤的改善的保护作用也被消除。最后，我们确定了IFNβ介导的MG表型调节在维持BBB完整性方面发挥了作用，因为MG中IFNAR 1的敲低部分逆转了IFNβ减轻延迟tPA处理的MCAO小鼠中BBB破坏的保护作用。总之，我们的研究揭示了IFNβ在调节MG表型中的新功能，并且随后可能对缺血性卒中中迟发性tPA加重的脑损伤提供保护。
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.
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影响因子：
4.6
作者：
Li YH;Fu HL;Tian ML;Wang YQ;Chen W;Cai LL;Zhou XH;Yuan HB
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DOI：
10.1084/jem.20080421
发表时间：
2008-09-29
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Getts DR;Terry RL;Getts MT;Müller M;Rana S;Shrestha B;Radford J;Van Rooijen N;Campbell IL;King NJ
通讯作者：
King NJ
影响因子：
3.9
作者：
Li, Qiu;Li, Qun;Hao, Zhihui;Zheng, Xucai;He, Wei
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影响因子：
4.7
作者：
Dixon BJ;Chen D;Zhang Y;Flores J;Malaguit J;Nowrangi D;Zhang JH;Tang J
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Tang J
影响因子：
9.8
作者：
He L;Vanlandewijck M;Mäe MA;Andrae J;Ando K;Del Gaudio F;Nahar K;Lebouvier T;Laviña B;Gouveia L;Sun Y;Raschperger E;Segerstolpe Å;Liu J;Gustafsson S;Räsänen M;Zarb Y;Mochizuki N;Keller A;Lendahl U;Betsholtz C
通讯作者：
Betsholtz C