Microglial cell loss after ischemic stroke favors brain neutrophil accumulation
Microglial cell loss after ischemic stroke favors brain neutrophil accumulation
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DOI：
10.1007/s00401-018-1954-4
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发表时间：
2019-02-01
影响因子：
12.7
通讯作者：
Planas, Anna M.
中科院分区：
文献类型：
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作者：
Otxoa-de-Amezaga, Amaia;Miro-Mur, Francesc;Planas, Anna M.
中风会将中性粒细胞吸引到受损的脑组织中，在那里它们可以破坏血脑屏障的完整性，加剧损伤。然而，涉及中性粒细胞在缺血脑内迁移、定位和积聚的机制尚未完全阐明。中性粒细胞穿过血管内皮细胞层和毛细血管后小静脉的内皮基底膜后，或从软脑膜迁移到脑血管周围间隙，或从软脑膜渗出和/或从颅骨骨髓转移到血管周围。根据先前对小胶质细胞吞噬中性粒细胞的观察，我们推测小胶质细胞可能控制了中性粒细胞在损伤脑内的聚集。我们研究了小鼠大脑中动脉永久性闭塞的模型，包括小胶质细胞和中性粒细胞报告小鼠。使用不同的体外和体内策略来损害小胶质细胞的功能或通过靶向集落刺激因子1受体(CSF1R)来消除小胶质细胞，本研究证明了中性粒细胞的小胶质细胞吞噬对缺血组织具有根本后果。我们发现，反应性小胶质细胞吞噬了缺血灶周围的中性粒细胞，而局部小胶质细胞的丢失和营养不良发生在缺血核心，与中性粒细胞首先聚集在血管周围空间，然后聚集在实质中有关。相应地，长期使用CSF1R抑制剂治疗的小胶质细胞枯竭增加了中性粒细胞的数量，扩大了缺血损伤。因此，小胶质细胞的吞噬功能设置了一条关键的防线，以抵御脑缺血时中性粒细胞对血管和组织的破坏能力。
Stroke attracts neutrophils to the injured brain tissue where they can damage the integrity of the blood-brain barrier and exacerbate the lesion. However, the mechanisms involved in neutrophil transmigration, location and accumulation in the ischemic brain are not fully elucidated. Neutrophils can reach the perivascular spaces of brain vessels after crossing the endothelial cell layer and endothelial basal lamina of post-capillary venules, or migrating from the leptomeninges following pial vessel extravasation and/or asuggestedtranslocation from the skull bone marrow. Based on previous observations of microglia phagocytosing neutrophils recruited to the ischemic brain lesion, we hypothesized that microglial cells might control neutrophil accumulation in the injured brain. We studied a model of permanent occlusion of the middle cerebral artery in mice, including microglia- and neutrophil-reporter mice. Using various in vitro and in vivo strategies to impair microglial function or to eliminate microglia by targeting colony stimulating factor 1 receptor (CSF1R), this study demonstrates that microglial phagocytosis of neutrophils has fundamental consequences for the ischemic tissue. We found that reactive microglia engulf neutrophils at the periphery of the ischemic lesion, whereas local microglial cell loss and dystrophy occurring in the ischemic core are associated with the accumulation of neutrophils first in perivascular spaces and later in the parenchyma. Accordingly, microglia depletion by long-term treatment with a CSF1R inhibitor increased the numbers of neutrophils and enlarged the ischemic lesion. Hence, microglial phagocytic function sets a critical line of defense against the vascular and tissue damaging capacity of neutrophils in brain ischemia.