Lemarchand Eloïse, Grayston Alba, Wong Raymond, Rogers Miyako, Ouvrier Blake, Llewellyn Benjamin, Webb Freddie, Lénárt Nikolett, Dénes Ádám, Brough David, Allan Stuart M, Bix Gregory J, Pinteaux Emmanuel
Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health (FBMH), The University of Manchester, Manchester, UK.
Geoffrey Jefferson Brain Research Centre, University of Manchester, Northern Care Alliance NHS Foundation Trust, The Manchester Academic Health Science Centre, Manchester, UK.
J Cereb Blood Flow Metab. 2025 Mar 20:271678X251323371. doi: 10.1177/0271678X251323371.
Inflammation is a key contributor to stroke pathogenesis and exacerbates brain damage leading to poor outcome. Interleukin-1 (IL-1) is an important regulator of post-stroke inflammation, and blocking its actions is beneficial in pre-clinical stroke models and safe in the clinical setting. However, the distinct roles of the two major IL-1 receptor type 1 agonists, IL-1α and IL-1β, and the specific role of IL-1α in ischemic stroke remain largely unknown. Here we show that IL-1α and IL-1β have different spatio-temporal expression profiles in the brain after experimental stroke, with early microglial IL-1α expression (4 h) and delayed IL-1β expression in infiltrated neutrophils and a small microglial subset (24-72 h). We examined for the first time the specific role of microglial-derived IL-1α in experimental permanent and transient ischemic stroke through microglial-specific tamoxifen-inducible Cre-loxP-mediated recombination. Microglial IL-1α deletion did not influence acute outcome after ischemic stroke. However, microglial IL-1α knock out (KO) mice showed reduced peri-infarct vessel density and reactive astrogliosis at 14 days post-stroke, alongside long-term impaired functional recovery. Our study identifies for the first time a critical role for microglial IL-1α on post-stroke neurorepair and recovery, highlighting the importance of targeting specific IL-1 mechanisms in brain injury to develop effective therapies.
炎症是中风发病机制的关键因素，会加剧脑损伤，导致预后不良。白细胞介素-1（IL-1）是中风后炎症的重要调节因子，在临床前中风模型中阻断其作用有益，且在临床环境中是安全的。然而，两种主要的IL-1受体1型激动剂IL-1α和IL-1β的不同作用，以及IL-1α在缺血性中风中的具体作用，在很大程度上仍不清楚。在这里，我们表明，实验性中风后，IL-1α和IL-1β在脑中具有不同的时空表达谱，早期小胶质细胞IL-1α表达（4小时），而浸润的中性粒细胞和一小部分小胶质细胞中IL-1β表达延迟（24 - 72小时）。我们首次通过小胶质细胞特异性他莫昔芬诱导的Cre-loxP介导的重组，研究了小胶质细胞衍生的IL-1α在实验性永久性和短暂性缺血性中风中的具体作用。小胶质细胞IL-1α缺失不影响缺血性中风后的急性预后。然而，小胶质细胞IL-1α基因敲除（KO）小鼠在中风后14天时梗死灶周围血管密度降低，反应性星形胶质细胞增生减少，同时长期功能恢复受损。我们的研究首次确定了小胶质细胞IL-1α在中风后神经修复和恢复中的关键作用，强调了针对脑损伤中特定IL-1机制开发有效治疗方法的重要性。
