Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
JCI Insight. 2018 Sep 20;3(18). doi: 10.1172/jci.insight.121560.
Stroke triggers a complex inflammatory process in which the balance between pro- and antiinflammatory mediators is critical for the development of the brain infarct. However, systemic changes may also occur in parallel with brain inflammation. Here we demonstrate that administration of recombinant IL-33, a recently described member of the IL-1 superfamily of cytokines, promotes Th2-type effects following focal ischemic stroke, resulting in increased plasma levels of Th2-type cytokines and fewer proinflammatory (3-nitrotyrosine+F4/80+) microglia/macrophages in the brain. These effects of IL-33 were associated with reduced infarct size, fewer activated microglia and infiltrating cytotoxic (natural killer-like) T cells, and more IL-10-expressing regulatory T cells. Despite these neuroprotective effects, mice treated with IL-33 displayed exacerbated post-stroke lung bacterial infection in association with greater functional deficits and mortality at 24 hours. Supplementary antibiotics (gentamicin and ampicillin) mitigated these systemic effects of IL-33 after stroke. Our findings highlight the complex nature of the inflammatory mechanisms differentially activated in the brain and periphery during the acute phase after ischemic stroke. The data indicate that a Th2-promoting agent can provide neuroprotection without adverse systemic effects when given in combination with antibiotics.
中风会引发复杂的炎症反应，其中促炎和抗炎介质之间的平衡对于脑梗死的发展至关重要。然而，全身变化也可能与脑炎症平行发生。在这里，我们证明了重组白细胞介素-33（一种最近被描述的白细胞介素-1 超家族细胞因子）的给药会促进局灶性缺血性中风后的 Th2 型效应，导致血浆中 Th2 型细胞因子水平升高，大脑中促炎（3-硝基酪氨酸+F4/80+）小胶质细胞/巨噬细胞减少。白细胞介素-33 的这些作用与梗死面积减小、激活的小胶质细胞和浸润性细胞毒性（自然杀伤样）T 细胞减少以及表达更多白细胞介素-10 的调节性 T 细胞有关。尽管有这些神经保护作用，但接受白细胞介素-33 治疗的小鼠在中风后出现了更严重的肺部细菌感染，同时在 24 小时时出现了更大的功能缺陷和死亡率。补充抗生素（庆大霉素和氨苄西林）减轻了中风后白细胞介素-33 的这些全身作用。我们的发现强调了在缺血性中风后急性阶段，大脑和外周中不同激活的炎症机制的复杂性质。数据表明，在与抗生素联合使用时，促 Th2 剂可以提供神经保护而没有不良的全身影响。
