Hyperforin Promotes Post-stroke Neuroangiogenesis via Astrocytic IL-6-Mediated Negative Immune Regulation in the Ischemic Brain
Hyperforin Promotes Post-stroke Neuroangiogenesis via Astrocytic IL-6-Mediated Negative Immune Regulation in the Ischemic Brain
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金丝桃素通过星形胶质细胞 IL-6 介导的缺血性负性免疫调节促进中风后神经血管生成
DOI：
10.3389/fncel.2019.00201
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发表时间：
2019-05
影响因子：
5.3
通讯作者：
Zhang Jiancheng
中科院分区：
文献类型：
--
作者：
Yao Hua;Zhang Yujing;Shu Huaqing;Xie Bing;Tao Yuanfa;Yuan Yin;Shang You;Yuan Shiying;Zhang Jiancheng
在我们之前的研究中，穿孔素已被证明能够促进缺血性中风后的血管生成和功能恢复。然而，所涉及的确切机制尚未完全阐明。在这项研究中，成年雄性小鼠进行短暂的大脑中动脉闭塞60分钟，然后再灌注28天。从缺血后14天（dpi）开始，每24小时向MCAO小鼠施用贯叶连翘素，持续2周。通过流式细胞术、实时荧光定量PCR（RT-qPCR）、免疫组化、Western blotting和功能检测等方法，探讨其在体内外的分子机制。我们的数据表明，贯叶金丝桃素增加星形胶质细胞白细胞介素（IL）-6在缺血半球通过TLR 4在28 dpi。星形胶质细胞IL-6在贯叶金丝桃素促进脑卒中后神经前体细胞增殖、神经元分化、血管生成和功能恢复的作用中起重要作用。此外，贯叶金丝桃素促进调节性T细胞（Tcells）向缺血半球的浸润，并以依赖于星形胶质细胞IL-6的方式增加Tregs衍生的细胞因子IL-10和转化生长因子-β（TGF-β）。星形胶质细胞IL-6对贯叶金丝桃素促进辅助性T细胞（Th）2型向缺血半球浸润的作用至关重要，而Th 2衍生的细胞因子IL-4相对于Th 1和Th 1衍生的细胞因子干扰素-γ（IFN-γ）在卒中恢复期间下降。CD 25 + T细胞耗竭后，贯叶金丝桃素对脑卒中后神经发生的促进作用减弱。此外，阻断IL-4和TGF-β可消除贯叶金丝桃素在卒中后神经发生、血管生成和功能恢复中的促进作用。我们的研究结果揭示了星形胶质细胞IL-6介导的负性免疫调节在贯叶金丝桃素促进中风后神经血管再生和功能恢复中的作用。
Hyperforin has been shown to be capable of promoting angiogenesis and functional recovery after ischemic stroke in our previous study. However, the exact mechanisms involved are not fully elucidated. In this study, adult male mice were subjected to 60-min transient middle cerebral artery occlusion followed by reperfusion for 28 days. Hyperforin was administrated to MCAO mice every 24 h for 2 weeks starting at 14 days post-ischemia (dpi). Then flow cytometry, quantitative Real-time PCR (RT-qPCR), western blotting, immunohistochemistry, and functional assays were performed to explore the molecular mechanisms in vivo and in vitro. Our data showed that hyperforin increased astrocytic interleukin (IL)-6 in the ischemic hemisphere via TLR4 at 28 dpi. The astrocytic IL-6 was essential to the promoting effects of hyperforin on the neural precursor cells proliferation, neuronal differentiation, angiogenesis, and functional recovery after stroke. Furthermore, hyperforin promoted the infiltration of regulatory T cells (Tregs) to the ischemic hemisphere and increased Tregs-derived cytokine IL-10 and transforming growth factor-β (TGF-β) in a manner that was dependent on astrocytic IL-6. Astrocytic IL-6 was critical to the role of hyperforin in promoting the infiltration of T-helper (Th) type 2 cells to the ischemic hemisphere and Th2-derived cytokine IL-4, relative to Th1 and Th1-derived cytokine interferon-γ (IFN-γ), which decreased during stroke recovery. After depletion of CD25+ Tregs, the promoting effects of hyperforin on post-stroke neurogenesis was attenuated. Moreover, blockade of IL-4 and TGF-β abrogated the promoting role of hyperforin in post-stroke neurogenesis, angiogenesis and functional recovery. Our results reveal a previously uncharacterized role of astrocytic IL-6-mediated negative immune regulation in the promoting effects of hyperforin on post-stroke neurovascular regeneration and functional recovery.
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