2023 神醫中心學術演講6 (實體+線上)
時間 : 上午11:00
地點 : 國衛院竹南院區/ 行政大樓B1第6會議室
主題 : Interferon-β promotes microglial polarization and modulates neuroinflammation in delayed tPA-exacerbated ischemic brain injury
講師 : Jui-Hung Jimmy Yen, Ph.D.
Associate Professor of Microbiology and Immunology Indiana University School of Medicine U.S.A.
|視訊系統 Webex : 會議連結
會議號 : 2519 772 6399 密碼: 0725
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 bloodbrain barrier (BBB) disruption and hemorrhagic transformation. Studies from our and other groups have shown that interferon beta (IFNβ) or type I IFN receptor (IFNAR1) signaling confers protection against ischemic stroke in preclinical models. Here, we further investigated whether IFNβ can be co-administered with tPA to alleviate delayed tPAinduced adverse effects in ischemic stroke. Furthermore, we assessed the effect of IFNβ on modulating phenotypes of microglia (MG) in ischemic stroke with delayed tPA treatment. To do that, mice were subjected to transient middle cerebral artery occlusion (MCAO) followed by delayed tPA treatment in the presence or absence of IFNβ.
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 was able to extend tPA therapeutic window to 4.5h post-injury in MCAO mice and that was accompanied with attenuated brain injury and lessened BBB disruption. Mechanistically, we identified that IFNβ modulated MG polarization, leading to the suppression of inflammatory MG phenotype but the promotion of ant-inflammatory MG phenotype, in delayed tPA-treated MCAO mice.
Notably, the beneficial effects of IFNβ on modulating MG polarization and ameliorating delayed tPA-exacerbated ischemic brain injury were abolished in MG-specific IFNAR1 knockdown MCAO mice. Finally, we found that IFNβmediated 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 animals. In summary, our study reveals a novel function of IFNβ on modulating MG phenotypes and that may subsequently confer protection against delayed tPA-exacerbated brain injury in ischemic stroke.
更新 : 2023-07-25