Frieler Ryan A, Chung Yutein, Ahlers Carolyn G, Gheordunescu George, Song Jianrui, Vigil Thomas M, Shah Yatrik M, Mortensen Richard M
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, United States.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, United States; Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, MI 48109, United States; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, United States.
Exp Neurol. 2017 Dec;298(Pt A):104-111. doi: 10.1016/j.expneurol.2017.08.016. Epub 2017 Aug 31.
Neutrophils respond rapidly to cerebral ischemia and are thought to contribute to inflammation-mediated injury during stroke. Using myeloid Mcl1 knockout mice as a model of genetic neutrophil deficiency, we investigated the contribution of neutrophils to stroke pathophysiology. Myeloid Mcl1 knockout mice were subjected to transient middle cerebral artery occlusion and infarct size was assessed by MRI after 24h reperfusion. Immune cell mobilization and infiltration was assessed by flow cytometry. We found that myeloid Mcl1 knockout mice had significantly reduced infarct size when compared to heterozygous and wild type control mice (MyMcl1: 78.0mm; MyMcl1: 83.4mm; MyMcl1: 55.1mm). This was accompanied by a nearly complete absence of neutrophils in the ischemic hemisphere of myeloid Mcl1 knockout mice. Although myeloid Mcl1 knockout mice were protected from cerebral infarction, no significant differences in neurological deficit or the mRNA expression of inflammatory genes (TNFα, IL-1β, and MCP1) were detected. Inhibition of neutrophil chemotaxis using CXCR2 pepducin treatment partially reduced neutrophil mobilization and recruitment to the brain after stroke, but did not reduce infarct size 24h after transient MCA occlusion. These data confirm that neutrophils have an important role in infarct development during stroke pathophysiology, and suggest that complete deficiency, but not partial inhibition, is necessary to prevent neutrophil-mediated injury during stroke.
中性粒细胞对脑缺血反应迅速，被认为在中风期间促成炎症介导的损伤。我们以髓系Mcl1基因敲除小鼠作为遗传性中性粒细胞缺乏模型，研究了中性粒细胞在中风病理生理学中的作用。对髓系Mcl1基因敲除小鼠进行短暂性大脑中动脉闭塞，再灌注24小时后通过磁共振成像评估梗死灶大小。通过流式细胞术评估免疫细胞的动员和浸润情况。我们发现，与杂合子和野生型对照小鼠相比，髓系Mcl1基因敲除小鼠的梗死灶大小显著减小（髓系Mcl1敲除小鼠：78.0立方毫米；杂合子：83.4立方毫米；野生型：55.1立方毫米）。与此同时，髓系Mcl1基因敲除小鼠缺血半球几乎完全没有中性粒细胞。尽管髓系Mcl1基因敲除小鼠对脑梗死具有保护作用，但未检测到神经功能缺损或炎症基因（TNFα、IL-1β和MCP1）的mRNA表达有显著差异。使用CXCR2肽导向药物治疗抑制中性粒细胞趋化性，可部分减少中风后中性粒细胞向脑内的动员和募集，但在短暂性大脑中动脉闭塞24小时后并未减小梗死灶大小。这些数据证实，中性粒细胞在中风病理生理学过程中的梗死灶形成中起重要作用，并表明完全缺乏而非部分抑制对于预防中风期间中性粒细胞介导的损伤是必要的。
