Innate immunity activation in the early brain injury period following subarachnoid hemorrhage
Innate immunity activation in the early brain injury period following subarachnoid hemorrhage
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DOI：
10.1186/s12974-019-1629-7
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发表时间：
2019-12-04
影响因子：
9.3
通讯作者：
Cailhier, Jean-Francois
中科院分区：
文献类型：
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作者：
Gris, Typhaine;Laplante, Patrick;Cailhier, Jean-Francois
背景：动脉瘤性蛛网膜下腔出血(SAH)是一种灾难性的疾病，其后果是灾难性的，包括高死亡率和幸存者的严重残疾。SAH后会诱发炎症，但天然免疫细胞的确切作用和表型仍未得到很好的描述。方法：C57BL/6J野生型小鼠蛛网膜下腔注血诱导蛛网膜下腔出血。分别于12h、第1、2、7天采集血样，用流式细胞仪和酶联免疫吸附试验(ELISA)评价SAH的全身炎症反应。收集、酶消化或固定脑组织，用流式细胞仪和免疫荧光分析浸润性炎症细胞和神经元死亡的特征。在第7天使用保持时间和足迹测试进行表型评估。结果：SAH后，全身IL-6水平迅速升高，而IL-10水平下降。中性粒细胞在脑和血液中均增加，反映SAH后局部和外周炎症。早期脑组织中有较多的促炎性单核细胞。星形胶质细胞和小胶质细胞的激活也增加，小鼠有严重的运动障碍，这与caspase-3阳性凋亡神经元的百分比增加有关。同样，我们发现SAH后患者的IL-6水平迅速升高。预后好与差的SAH患者ICAM-1、bFGF、IL-7、IL-12p40和MCP-4随时间的变化不同。此外，入院时Flt-1和VEGF水平升高与预后不良有关。结论：SAH可导致脑内早期浸润和外周天然免疫细胞活化。此外，小胶质细胞和星形胶质细胞的激活出现在较晚的时间点。我们的人类和小鼠数据表明，SAH是一种全身性炎症性疾病，免疫细胞代表着潜在的治疗靶点，以帮助这类需要新治疗的患者。
Background: Aneurysmal subarachnoid hemorrhage (SAH) is a catastrophic disease with devastating consequences, including a high mortality rate and severe disabilities among survivors. Inflammation is induced following SAH, but the exact role and phenotype of innate immune cells remain poorly characterized. We investigated the inflammatory components of the early brain injury in an animal model and in SAH patients.Method: SAH was induced through injection of blood in the subarachnoid space of C57Bl/6 J wild-type mice. Prospective blood collections were obtained at 12 h, days 1, 2, and 7 to evaluate the systemic inflammatory consequences of SAH by flow cytometry and enzyme-linked immunosorbent-assay (ELISA). Brains were collected, enzymatically digested, or fixed to characterize infiltrating inflammatory cells and neuronal death using flow cytometry and immunofluorescence. Phenotypic evaluation was performed at day 7 using the holding time and footprint tests. We then compared the identified inflammatory proteins to the profiles obtained from the plasma of 13 human SAH patients.Results: Following SAH, systemic IL-6 levels increased rapidly, whereas IL-10 levels were reduced. Neutrophils were increased both in the brain and in the blood reflecting local and peripheral inflammation following SAH. More intracerebral pro-inflammatory monocytes were found at early time points. Astrocyte and microglia activation were also increased, and mice had severe motor deficits, which were associated with an increase in the percentage of caspase-3-positive apoptotic neurons. Similarly, we found that IL-6 levels in patients were rapidly increased following SAH. ICAM-1, bFGF, IL-7, IL-12p40, and MCP-4 variations over time were different between SAH patients with good versus bad outcomes. Moreover, high levels of Flt-1 and VEGF at admission were associated with worse outcomes.Conclusion: SAH induces an early intracerebral infiltration and peripheral activation of innate immune cells. Furthermore, microglia and astrocytic activation are present at later time points. Our human and mouse data illustrate that SAH is a systemic inflammatory disease and that immune cells represent potential therapeutic targets to help this population of patients in need of new treatments.