Interleukin-4 Is Essential for Microglia/Macrophage M2 Polarization and Long-Term Recovery After Cerebral Ischemia.
Interleukin-4 Is Essential for Microglia/Macrophage M2 Polarization and Long-Term Recovery After Cerebral Ischemia.
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Interleukin-4 对于小胶质细胞/巨噬细胞 M2 极化和脑缺血后的长期恢复至关重要
DOI：
10.1161/strokeaha.115.012079
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发表时间：
2016-02
期刊：
影响因子：
8.3
通讯作者：
Hu X
中科院分区：
文献类型：
--
作者：
Liu X;Liu J;Zhao S;Zhang H;Cai W;Cai M;Ji X;Leak RK;Gao Y;Chen J;Hu X
白细胞介素-4 （IL-4）是一种独特的细胞因子，可能通过调节小胶质细胞/巨噬细胞的功能来促进脑修复。因此，我们在两种成熟的脑卒中模型中研究了IL-4对长期恢复和小胶质细胞/巨噬细胞极化的影响。在野生型（WT）和IL-4敲除（KO） C57/BL6小鼠中诱导短暂性大脑中动脉闭塞（tMCAO）或永久性远端大脑中动脉闭塞（dMCAO）。在另一组WT动物中，在tMCAO后向脑室注入IL-4 （60 ng/d，连续7d）或对照物。行为结果通过rotard、corner、foot fault和Morris水迷宫测试进行评估。两个独立的神经元标记物证实了神经元组织的丢失。采用RT-PCR、免疫荧光和流式细胞术评估经典活化（M1）和交替活化（M2）小胶质细胞的标志物。损伤后21天，IL-4的缺失加重了感觉运动缺陷和认知功能受损。与延迟性神经功能恶化相反，IL-4缺乏仅在脑卒中后急性期（5d）增加神经元组织损失，对损伤后14d或21d的神经元组织损失无影响。IL-4的缺失促进了M1小胶质细胞/巨噬细胞标志物的表达，并在损伤后5d和14d损害了M2标志物的表达。IL-4注入缺血脑也能促进长期功能恢复。细胞因子IL-4可能通过诱导小胶质细胞/巨噬细胞M2表型改善脑卒中后的长期神经预后。这些结果首次表明，用IL-4进行免疫调节是促进中风后长期功能恢复的一种有希望的方法。
Interleukin-4 (IL-4) is a unique cytokine that may contribute to brain repair by regulating microglia/macrophage functions. Thus, we examined the effect of IL-4 on long-term recovery and microglia/macrophage polarization in two well-established stroke models. Transient middle cerebral artery occlusion (tMCAO) or permanent distal MCAO (dMCAO) was induced in wild-type (WT) and IL-4 knockout (KO) C57/BL6 mice. In a separate cohort of WT animals, IL-4 (60 ng/d for 7d) or vehicle was infused into the cerebroventricle after tMCAO. Behavioral outcomes were assessed by the Rotarod, corner, foot fault, and Morris water maze tests. Neuronal tissue loss was verified by two independent neuron markers. Markers of classically activated (M1) and alternatively activated (M2) microglia were assessed by RT-PCR, immunofluorescence, and flow cytometry. Loss of IL-4 exacerbated sensorimotor deficits and impaired cognitive functions up to 21d post-injury. In contrast to the delayed deterioration of neurological functions, IL-4 deficiency increased neuronal tissue loss only in the acute phase (5d) after stroke and had no impact on neuronal tissue loss 14d or 21d post-injury. Loss of IL-4 promoted expression of M1 microglia/macrophage markers and impaired expression of M2 markers at 5d and 14d post-injury. Administration of IL-4 into the ischemic brain also enhanced long-term functional recovery. The cytokine IL-4 improves long-term neurological outcomes after stroke, perhaps through M2 phenotype induction in microglia/macrophages. These results are the first to suggest that immunomodulation with IL-4 is a promising approach to promote long-term functional recovery after stroke.