Neuronal IL-4Rα modulates neuronal apoptosis and cell viability during the acute phases of cerebral ischemia.
Neuronal IL-4Rα modulates neuronal apoptosis and cell viability during the acute phases of cerebral ischemia.
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DOI：
10.1111/febs.14498
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Marchuk DA
中科院分区：
文献类型：
--
作者：
Lee HK;Koh S;Lo DC;Marchuk DA
由栓塞或局部血栓形成引起的缺血性卒中导致闭塞脑动脉区域的神经组织损伤（梗死）。数十年的研究增加了我们对脑梗死过程中分子事件的理解;然而，将这些发现转化为缺血性卒中治疗的可药用靶点在很大程度上令人失望。白细胞介素-4（IL-4）是一种多功能细胞因子，通过白细胞介素-4受体α（IL-4 R α）发挥其细胞活性。该受体复合物与多种免疫和炎症反应相关。最近的研究表明，细胞因子IL-4在长期缺血性卒中恢复中的作用，涉及免疫细胞活性。相比之下，受体IL-4 R α的作用，特别是在梗死急性期的作用尚不清楚。在这项研究中，我们确定了IL-4 R α在神经元上表达，并且在脑梗死的早期阶段（24小时），该受体的水平增加，以通过激活STAT 6来调节细胞凋亡因子。在这种情况下，我们显示了IL-4 R α在脑缺血的体内手术模型和离体脑切片外植体中的神经保护作用，使用该受体的基因敲除和RNAi介导的基因敲除。因此，IL-4 R α可能代表缺血性卒中治疗开发的新靶点和途径。在这项研究中，我们报告了小鼠脑中的神经元表达IL-4 R α，并且在缺血性卒中的早期阶段（24小时内），该受体的水平增加，通过激活STAT 6来调节细胞凋亡因子。因此，IL-4 R α在缺血性脑卒中急性期的神经保护中发挥细胞自主性作用。
Ischemic stroke caused by an embolus or local thrombosis results in neural tissue damage (an infarct) in the territory of the occluded cerebral artery. Decades of studies have increased our understanding of the molecular events during cerebral infarction; however, translation of these discoveries to druggable targets for ischemic stroke treatment has been largely disappointing. Interleukin-4 (IL-4) is a multifunctional cytokine that exerts its cellular activities via the interleukin-4 receptor α (IL-4Rα). This cytokine-receptor complex is associated with diverse immune and inflammatory responses. Recent studies have suggested a role of the cytokine IL-4 in long-term ischemic stroke recovery, involving immune cell activity. By contrast, the role of the receptor, IL-4Rα especially in the acute phase of infarction is unclear. In this study, we determined that IL-4Rα is expressed on neurons and that during the early phases of cerebral infarction (24 hours) levels of this receptor are increased to regulate cellular apoptosis factors through activation of STAT6. In this context, we show a neuroprotective role for IL-4Rα in an in vivo surgical model of cerebral ischemia and in ex vivo brain slice explants, using both genetic knockout of this receptor and RNAi-mediated gene knockdown. IL-4Rα may therefore represent a novel target and pathway for therapeutic development in ischemic stroke. In this study, we report that neurons in the mouse brain express IL-4Rα and that during the early phase of ischemic stroke (within 24 hours), levels of this receptor are increased to regulate cellular apoptotic factors through activation of STAT6. Therefore, IL-4Rα plays a cell autonomous role in neuroprotection in the acute phase of ischemic stroke.
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影响因子：
4.5
作者：
Keum S;Lee HK;Chu PL;Kan MJ;Huang MN;Gallione CJ;Gunn MD;Lo DC;Marchuk DA
通讯作者：
Marchuk DA
DOI：
10.1126/science.aaj2067
发表时间：
2017-06-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Minutti CM;Jackson-Jones LH;García-Fojeda B;Knipper JA;Sutherland TE;Logan N;Ringqvist E;Guillamat-Prats R;Ferenbach DA;Artigas A;Stamme C;Chroneos ZC;Zaiss DM;Casals C;Allen JE
通讯作者：
Allen JE
影响因子：
8.3
作者：
Bevan, Steve;Traylor, Matthew;Markus, Hugh S.
通讯作者：
Markus, Hugh S.
影响因子：
4.8
作者：
Elkind, Mitchell S. V.
通讯作者：
Elkind, Mitchell S. V.
DOI：
10.1073/pnas.94.20.10838
发表时间：
1997-09-30
影响因子：
11.1
作者：
NobenTrauth, N;Shultz, LD;Paul, WE
通讯作者：
Paul, WE