Unravelling the role of cell-specific interleukin-1B during cerebrovascular inflammation after stroke

白介素1(IL-1)促进中风后的炎症，导致脑损伤和较差的预后。在临床前的中风模型中，用IL-1受体拮抗剂(IL-1ra)阻断IL-1的作用是有益的，在中风患者中的研究表明，IL-1ra是安全的，可能会改善临床结果。重要的是，IL-1以两种亚型表达，即IL-1α(IL-1a)和IL-1β(IL-1b)，但每个配体在卒中中的具体功能尚不清楚。我们最近建立了新的条件性IL-1基因小鼠模型，以准确地识别IL-1a和IL-1b在中风中的相对贡献。这可以通过选择性地删除中风后导致炎症的关键脑细胞(主要是内皮细胞、小胶质细胞和神经元)中的每个IL-1成员来实现，并评估基因缺失对脑血管炎症和中风预后的影响。我们最近的初步实验表明，IL-1B(卒中后神经炎症的主要驱动因素)在卒中后的一部分小胶质细胞和浸润性中性粒细胞中表达，但小胶质细胞和中性粒细胞来源的IL-1B在卒中中的作用尚不清楚。本项目的目的是通过结合体外和体内脑缺血模型以及大量强大的分子、细胞和成像分析技术，分析IL-1B在小胶质细胞和中性粒细胞中选择性缺失对卒中结局、脑血管炎症机制、长期血管修复和功能恢复的影响，进一步探讨IL-1B在中风中的确切病理生理功能。该项目的最终目的是为了更好地了解IL-1B在中风后炎症过程中潜在的神经保护和神经修复作用，以便更好地进行治疗干预。

Interleukin-1 (IL-1) drives inflammation after stroke, contributing to brain damage and poorer outcome. Blocking IL-1 actions with the IL-1 receptor antagonist (IL-1Ra) is beneficial in pre-clinical stroke models, and studies in stroke patients show that IL-1Ra is safe and may improve clinical outcomes. Importantly, IL-1 is expressed as two isoforms, IL-1 alpha (IL-1a) and IL-1 beta (IL-1B), but the specific function of each ligand in stroke is completely unknown. We have recently generated new conditional IL-1 genetic mouse models to precisely identify the relative contribution of IL-1a and IL-1B during stroke. This can be achieved by selectively deleting each of those IL-1 members in key brain cells that are known to contribute to inflammation after stroke (primarily endothelial cells, microglia and neurons), and to assess the effect of gene deletion on cerebrovascular inflammation and stroke outcome. Our recent preliminary experiments demonstrated that IL-1B (main driver of neuroinflammation after stroke) is expressed in a subset of microglia and infiltrating neutrophils after stroke but the function of microglial- and neutrophil-derived IL-1B in stroke is completely unknown. The aim of the project is to further explore the precise pathophysiological function of IL-1B in stroke by analysing the effect of selective deletion of IL-1B in microglia and neutrophils on stroke outcome, mechanisms of cerebrovascular inflammation, long term vascular repair and functional recovery, using a combination of in vitro and in vivo models of cerebral ischaemia, as well as a large array of powerful molecular, cellular and imaging analytical techniques. The ultimate aim of the project is to provide a better insight into the potential neuroprotective and neuroreparative role of IL-1B during post stroke inflammation for better therapeutic interventions.