Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy.
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Nat Immunol. 2023 Jun;24(6):925-940. doi: 10.1038/s41590-023-01505-1. Epub 2023 May 15.
Aging accounts for increased risk and dismal outcome of ischemic stroke. Here, we investigated the impact of age-related changes in the immune system on stroke. Upon experimental stroke, compared with young mice, aged mice had increased neutrophil clogging of the ischemic brain microcirculation, leading to worse no-reflow and outcomes. Aged mice showed an enhanced granulopoietic response to stroke that led to the accumulation of CD101CD62L mature and CD177CD101CD62L and CD177CD101CD62L immature atypical neutrophils in the blood, endowed with increased oxidative stress, phagocytosis and procoagulant features. Production of CXCL3 by CD62L neutrophils of the aged had a key role in the development and pathogenicity of aging-associated neutrophils. Hematopoietic stem cell rejuvenation reverted aging-associated neutropoiesis and improved stroke outcome. In elderly patients with ischemic stroke, single-cell proteome profile of blood leukocytes identified CD62L neutrophil subsets associated with worse reperfusion and outcome. Our results unveil how stroke in aging leads to a dysregulated emergency granulopoiesis impacting neurological outcome.
衰老导致缺血性中风的风险增加和预后不良。在这里，我们研究了免疫系统与年龄相关的变化对中风的影响。在实验性中风后，与年轻小鼠相比，老年小鼠缺血性大脑微循环中的中性粒细胞堵塞增加，导致再灌注不良和预后更差。老年小鼠对中风表现出增强的粒状生成反应，导致血液中积累 CD101CD62L 成熟和 CD177CD101CD62L 和 CD177CD101CD62L 不成熟的非典型中性粒细胞，具有增加的氧化应激、吞噬作用和促凝特性。老年 CD62L 中性粒细胞产生的 CXCL3 在衰老相关中性粒细胞的发展和发病机制中起关键作用。造血干细胞再生恢复了与衰老相关的中性粒细胞生成，并改善了中风的结果。在患有缺血性中风的老年患者中，血液白细胞的单细胞蛋白质组谱鉴定出与再灌注和预后不良相关的 CD62L 中性粒细胞亚群。我们的研究结果揭示了中风如何导致失调的应急粒细胞生成，从而影响神经学结果。
