Essential role of interleukin-6 in post-stroke angiogenesis
Essential role of interleukin-6 in post-stroke angiogenesis
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DOI：
10.1093/brain/aws075
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发表时间：
2012-06-01
期刊：
影响因子：
14.5
通讯作者：
Endres, Matthias
中科院分区：
文献类型：
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作者：
Gertz, Karen;Kronenberg, Golo;Endres, Matthias
白细胞介素-6对缺血性卒中发病机制的矛盾作用已有报道。然而，迄今为止，脑卒中后白细胞介素-6的长期作用尚未研究。在这里，我们进行了白细胞介素-6基因敲除（IL-6（-/-））和野生型对照小鼠轻度脑缺血30分钟丝状大脑中动脉闭塞/再灌注。虽然缺血性组织损伤在早期时间点相当，但IL-6（-/-）小鼠显示慢性病变体积显著增加以及长期功能结局更差。特别是，IL-6（-/-）小鼠表现出对脑缺血的血管生成反应受损，4周时新生成的内皮细胞数量减少，灌注微血管密度降低沿着局部脑血流量绝对值降低，缺血纹状体血管反应性降低。类似地，血管生成相关基因网络的早期基因组激活强烈减少，并且在野生型小鼠中观察到的缺血诱导的信号转导子和转录激活子3激活在IL-6（-/-）小鼠中几乎不存在。此外，在IL-6（-/-）小鼠中，系统性新血管生成受损。将白细胞介素-6活性骨髓移植到IL-6（-/-）小鼠（IL-6（chi））中并不能拯救中风后白细胞介素-6信使RNA的表达或血管生成的早期转录激活。因此，IL-6（chi）小鼠的慢性卒中结果概括了白细胞介素-6缺乏对卒中后再生的主要影响，病变体积显著增加，血管密度降低。额外的体外实验产生了补充证据，这表明中风后，常驻脑细胞在自我放大网络中充当白细胞介素-6的主要来源。在每种情况下，用白细胞介素6处理初级皮质神经元、混合神经胶质细胞培养物或永生化脑内皮细胞诱导了稳健的白细胞介素-6信使RNA转录，而氧-葡萄糖剥夺则没有。然而，器官型脑切片的氧-葡萄糖剥夺导致白细胞介素-6信使RNA沿着关键血管生成相关基因的转录增加。总之，由脑细胞局部产生的白细胞介素-6促进中风后血管生成，从而提供长期的组织学和功能保护。
Ambivalent effects of interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of interleukin-6 after stroke have not been investigated. Here, we subjected interleukin-6 knockout (IL-6(-/-)) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6(-/-) mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6(-/-) mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6(-/-) mice. In addition, systemic neoangiogenesis was impaired in IL-6(-/-) mice. Transplantation of interleukin-6 competent bone marrow into IL-6(-/-) mice (IL-6(chi)) did not rescue interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6(chi) mice recapitulated the major effects of interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with interleukin 6-induced robust interleukin-6 messenger RNA transcription in each case, whereas oxygen-glucose deprivation did not. However, oxygen-glucose deprivation of organotypic brain slices resulted in strong upregulation of interleukin-6 messenger RNA along with increased transcription of key angiogenesis-associated genes. In conclusion, interleukin-6 produced locally by resident brain cells promotes post-stroke angiogenesis and thereby affords long-term histological and functional protection.