Cui Pan, Song Bo, Xia Zongping, Xu Yuming
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.
NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Diseases, Zhengzhou, Henan, China.
Transl Stroke Res. 2025 Jun;16(3):962-974. doi: 10.1007/s12975-024-01236-x. Epub 2024 Mar 11.
Type I interferon (IFN-I) signalling is intricately involved in the pathogenesis of multiple infectious diseases, autoimmune diseases, and neurological diseases. Acute ischemic stroke provokes overactivation of IFN-I signalling within the injured brain, particularly in microglia. Following cerebral ischemia, damage-associated molecular patterns (DAMPs) released from injured neural cells elicit marked proinflammatory episodes within minutes. Among these, self-nucleic acids, including nuclear DNA and mitochondrial DNA (mtDNA), have been recognized as a critical alarm signal to fan the flames of neuroinflammation, predominantly via inducing IFN-I signalling activation in microglia. The concept of interferon-responsive microglia (IRM), marked by upregulation of a plethora of IFN-stimulated genes, has been emergingly elucidated in ischemic mouse brains, particularly in aged ones. Among the pattern recognition receptors responsible for IFN-I induction, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays integral roles in potentiating microglia-driven neuroinflammation and secondary brain injury after cerebral ischemia. Here, we aim to provide an up-to-date review on the multifaceted roles of IFN-I signalling, the detailed molecular and cellular mechanisms leading to and resulting from aberrant IFN-I signalling activation after cerebral ischemia, and the therapeutic potentials. A thorough exploration of these above points will inform our quest for IFN-based therapies as effective immunomodulatory therapeutics to complement the limited repertoire of thrombolytic agents, thereby facilitating the translation from bench to bedside.
I型干扰素（IFN-I）信号通路与多种传染病、自身免疫性疾病和神经疾病的发病机制密切相关。急性缺血性中风会引发受损脑内IFN-I信号通路的过度激活，尤其是在小胶质细胞中。脑缺血后，受损神经细胞释放的损伤相关分子模式（DAMP）在数分钟内引发明显的促炎反应。其中，包括核DNA和线粒体DNA（mtDNA）在内的自身核酸已被认为是加剧神经炎症的关键警报信号，主要是通过诱导小胶质细胞中的IFN-I信号通路激活来实现。干扰素反应性小胶质细胞（IRM）的概念已在缺血性小鼠脑中逐渐明晰，其特征是大量干扰素刺激基因上调，在老年小鼠脑中尤为明显。在负责诱导IFN-I的模式识别受体中，环磷酸鸟苷-腺苷酸合成酶（cGAS）-干扰素基因刺激物（STING）在增强小胶质细胞驱动的神经炎症和脑缺血后的继发性脑损伤中发挥着不可或缺的作用。在此，我们旨在对IFN-I信号通路的多方面作用、脑缺血后异常IFN-I信号通路激活的详细分子和细胞机制以及治疗潜力进行最新综述。对上述要点的深入探索将为我们寻求基于IFN的疗法提供参考，作为有效的免疫调节疗法来补充溶栓药物有限的种类，从而促进从 bench 到 bedside 的转化。
