Aldose Reductase Regulates Microglia/Macrophages Polarization Through the cAMP Response Element-Binding Protein After Spinal Cord Injury in Mice
Aldose Reductase Regulates Microglia/Macrophages Polarization Through the cAMP Response Element-Binding Protein After Spinal Cord Injury in Mice
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小鼠脊髓损伤后醛糖还原酶通过 cAMP 响应元件结合蛋白调节小胶质细胞/巨噬细胞极化
DOI：
10.1007/s12035-014-9035-8
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发表时间：
2014-12
影响因子：
5.1
通讯作者：
Wang, Jian
中科院分区：
文献类型：
--
作者：
Chung, Sookja K.;Song, Bing;Ju, Gong;Wang, Jian
炎症反应是脊髓损伤后最重要的病理过程。活化的小胶质细胞/巨噬细胞基于其功能极化的M1/M2亚群对神经再生具有有害或有益的影响。然而，小胶质细胞/巨噬细胞在受损脊髓环境中极化为M1/M2的机制仍然未知。在这项研究中，野生型（WT）或醛糖还原酶（AR）基因敲除（KO）小鼠通过脊髓挤压损伤模型进行SCI。在SCI后4小时至28天评估AR的表达模式、自发活动的行为测试和病变大小。我们发现WT小鼠SCI后小胶质细胞/巨噬细胞中AR的表达上调。在AR KO小鼠中，与WT相比，SCI导致更小的损伤病变面积。AR缺陷诱导的小胶质细胞/巨噬细胞诱导M2而不是M1反应，并促进小鼠SCI后的运动恢复。在体外实验中，用AR抑制剂（ARI）非达司他处理小胶质细胞系（N9或BV 2）。AR抑制引起4-羟基壬烯醛（HNE）的积累，这诱导cAMP反应元件结合蛋白（CREB）的磷酸化，以促进Arg 1的表达。磷酸化CREB的特异性抑制剂KG 501可取消ARI或HNE对Arg 1的上调作用。我们的研究结果表明，AR作为一个开关，可以调节小胶质细胞极化细胞的M1或M2表型下M1刺激的基础上，其活动状态。我们认为，抑制AR可能是一个有前途的治疗方法在未来的SCI。
Inflammatory reactions are the most critical pathological processes occurring after spinal cord injury (SCI). Activated microglia/macrophages have either detrimental or beneficial effects on neural regeneration based on their functional polarized M1/M2 subsets. However, the mechanism of microglia/macrophage polarization to M1/M2 at the injured spinal cord environment remains unknown. In this study, wild-type (WT) or aldose reductase (AR)-knockout (KO) mice were subjected to SCI by a spinal crush injury model. The expression pattern of AR, behavior tests for locomotor activity, and lesion size were assessed at between 4 h and 28 days after SCI. We found that the expression of AR is upregulated in microglia/macrophages after SCI in WT mice. In AR KO mice, SCI led to smaller injury lesion areas compared to WT. AR deficiency-induced microglia/macrophages induce the M2 rather than the M1 response and promote locomotion recovery after SCI in mice. In the in vitro experiments, microglia cell lines (N9 or BV2) were treated with the AR inhibitor (ARI) fidarestat. AR inhibition caused 4-hydroxynonenal (HNE) accumulation, which induced the phosphorylation of the cAMP response element-binding protein (CREB) to promote Arg1 expression. KG501, the specific inhibitor of phosphorylated CREB, could cancel the upregulation of Arg1 by ARI or HNE stimulation. Our results suggest that AR works as a switch which can regulate microglia by polarizing cells to either the M1 or the M2 phenotype under M1 stimulation based on its states of activity. We suggest that inhibiting AR may be a promising therapeutic method for SCI in the future.
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影响因子：
4.2
作者：
Carrico, Kimberly M.;Vaishnav, Radhika;Hall, Edward D.
通讯作者：
Hall, Edward D.
影响因子：
4
作者：
F. Vaillancourt;B. Morquette;Q. Shi;H. Fahmi;P. Lavigne;J. D. Di Battista;J. Fernandes;M. Benderdour
通讯作者：
F. Vaillancourt;B. Morquette;Q. Shi;H. Fahmi;P. Lavigne;J. D. Di Battista;J. Fernandes;M. Benderdour
影响因子：
7.7
作者：
Ho, Eric C. M.;Lam, Karen S. L.;Chung, Sookja K.
通讯作者：
Chung, Sookja K.
影响因子：
5.3
作者：
Ho, HTB;Chung, SK;Chung, SSM
通讯作者：
Chung, SSM
影响因子：
7.7
作者：
Price, SA;Agthong, S;Tomlinson, DR
通讯作者：
Tomlinson, DR