Vitronectin mitigates stroke-increased neurogenesis only in female mice and through FAK-regulated IL-6.
Vitronectin mitigates stroke-increased neurogenesis only in female mice and through FAK-regulated IL-6.
复制标题
玻连蛋白仅通过 FAK 调节的 IL-6 减轻雌性小鼠因中风而增加的神经发生。
DOI：
10.1016/j.expneurol.2019.113088
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发表时间：
2020
影响因子：
5.3
通讯作者：
Hagg,Theo
中科院分区：
文献类型：
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作者：
Jia,Cuihong;Keasey,MatthewP;Malone,HannahM;Lovins,Chiharu;Hagg,Theo
玻连蛋白（Vitronectin，VTN）是一种主要由肝脏产生的血液蛋白。我们发现，在成年小鼠缺血性中风（大脑中动脉闭塞，MCAO）后，VTN从血流中泄漏到损伤部位和邻近的室下区（SVZ）。已知MCAO会增加中风后的神经发生。VTN抑制了雌性的这种反应，但在雄性中没有，如雌性VTN−/−小鼠在14 d时中风诱导的SVZ神经发生增加约70%所示。在雌性VTN−/−小鼠中，24 h时SVZ中卒中诱导的白细胞介素-6（IL-6）表达减少。密切相关的白血病抑制因子（LIF）或前神经源性睫状神经营养因子（CNTF）没有受到影响。卵巢切除和去势显示，VTN对IL-6表达的女性特异性影响不是由于性激素。在SVZ附近注射IL-6逆转了VTN−/−小鼠中观察到的MCAO诱导的神经发生增加。我们的体外和体内数据表明，血浆VTN激活局灶性粘附激酶（FAK）在SVZ后MCAO，这减少了星形胶质细胞中的IL-6表达，但增加了它在其他细胞，如小胶质细胞/巨噬细胞。诱导条件性星形胶质细胞FAK缺失增加MCAO诱导的IL-6表达的女性在24小时和阻断MCAO诱导的神经发生在14天，证实了IL-6的关键有害作用。总的来说，这些数据表明，VTN泄漏到SVZ通过促进IL-6表达来减少雌性小鼠对中风的神经原性反应。减少VTN或VTN信号可能是促进女性卒中后神经发生的神经保护和细胞替代的方法。
Vitronectin (VTN) is a blood protein produced mainly by the liver. We show that VTN leaks from the bloodstream into the injury site and neighboring subventricular zone (SVZ) following ischemic stroke (middle cerebral artery occlusion, MCAO) in adult mice. MCAO is known to increase neurogenesis after stroke. VTN inhibits this response in females, but not in males, as shown by ~70% more stroke-induced SVZ neurogenesis in female VTN−/− mice at 14 d. In female VTN−/− mice, stroke-induced expression of interleukin-6 (IL-6) at 24 h was reduced in the SVZ. The closely related leukemia inhibitory factor (LIF) or pro-neurogenic ciliary neurotrophic factor (CNTF) were not affected. The female-specific effect of VTN on IL-6 expression was not due to sex hormones, as shown by ovariectomy and castration. IL-6 injection next to the SVZ reversed the MCAO-induced increase in neurogenesis seen in VTN−/− mice. Our in vitro and vivo data suggest that plasma VTN activates focal adhesion kinase (FAK) in the SVZ following MCAO, which reduces IL-6 expression in astrocytes but increases it in other cells such as microglia/macrophages. Inducible conditional astrocytic FAK deletion increased MCAO-induced IL-6 expression in females at 24 h and blocked MCAO-induced neurogenesis at 14 d, confirming a key detrimental role of IL-6. Collectively, these data suggest that leakage of VTN into the SVZ reduces the neurogenic response to stroke in female mice by promoting IL-6 expression. Reducing VTN or VTN signaling may be an approach to promote neurogenesis for neuroprotection and cell replacement after stroke in females.