Natural allelic variation of the IL-21 receptor modulates ischemic stroke infarct volume
Natural allelic variation of the IL-21 receptor modulates ischemic stroke infarct volume
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DOI：
10.1172/jci84491
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发表时间：
2016-08-01
影响因子：
15.9
通讯作者：
Marchuk, Douglas A.
中科院分区：
文献类型：
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作者：
Lee, Han Kyu;Keum, Sehoon;Marchuk, Douglas A.
缺血性中风的风险有很强的遗传基础，但可遗传因素也会影响中风发生后的损害程度。我们先前在小鼠7号染色体远端发现了一个基因座，该基因座对近交系间观察到的缺血后脑梗塞体积变异的贡献率超过50%。在这里，我们使用祖先单倍型分析，最终将该基因定位到12个候选基因。编码IL-21受体(Il21r)的基因在新生儿和成人的皮质组织中显示出明显不同的菌株特异性转录水平和编码变体。在Il21r基因缺陷的小鼠中，侧支血管连接适度减少，脑梗塞体积增加2.3倍，表明Il21r既调节侧支血管解剖，又调节天然神经保护。在脑片外植体中，与对照组相比，缺氧(OD)激活了IL-21受体缺陷(IL-21R)小鼠的细胞凋亡途径，增加了神经细胞死亡。我们确定IL-21R的神经保护作用来源于JAK/STAT信号通路和caspase-3的上调。因此，小鼠IL21R的自然遗传变异通过调节受体功能和下游信号转导来影响缺血后神经细胞的活性。基于自然发生的等位基因变异识别神经保护基因有可能为开发治疗缺血性中风的药物靶点提供信息。
Risk for ischemic stroke has a strong genetic basis, but heritable factors also contribute to the extent of damage after a stroke has occurred. We previously identified a locus on distal mouse chromosome 7 that contributes over 50% of the variation in postischemic cerebral infarct volume observed between inbred strains. Here, we used ancestral haplotype analysis to finemap this locus to 12 candidate genes. The gene encoding the IL-21 receptor (Il21r) showed a marked difference in strain-specific transcription levels and coding variants in neonatal and adult cortical tissue. Collateral vessel connections were moderately reduced in Il21r-deficient mice, and cerebral infarct volume increased 2.3-fold, suggesting that Il21r modulates both collateral vessel anatomy and innate neuroprotection. In brain slice explants, oxygen deprivation (OD) activated apoptotic pathways and increased neuronal cell death in IL-21 receptor-deficient (IL-21R-deficient) mice compared with control animals. We determined that the neuroprotective effects of IL-21R arose from signaling through JAK/STAT pathways and upregulation of caspase 3. Thus, natural genetic variation in murine Il21r influences neuronal cell viability after ischemia by modulating receptor function and downstream signal transduction. The identification of neuroprotective genes based on naturally occurring allelic variations has the potential to inform the development of drug targets for ischemic stroke treatment.