Department of Neurobiology, The Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, China.
Department of Anatomy, The University of Hong Kong, HKSAR, China.
Mol Neurobiol. 2016 Jan;53(1):662-676. doi: 10.1007/s12035-014-9035-8. Epub 2014 Dec 19.
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.
炎症反应是脊髓损伤 (SCI) 后发生的最关键的病理过程。基于其功能性极化的 M1/M2 亚群，活化的小胶质细胞/巨噬细胞对神经再生既有有害作用，也有有益作用。然而，在损伤的脊髓环境中小胶质细胞/巨噬细胞向 M1/M2 极化的机制尚不清楚。在这项研究中，野生型 (WT) 或醛糖还原酶 (AR)-敲除 (KO) 小鼠通过脊髓挤压伤模型接受 SCI。在 SCI 后 4 h 至 28 d 评估 AR 的表达模式、运动活动行为测试和损伤大小。我们发现，在 WT 小鼠的 SCI 后，AR 在小胶质细胞/巨噬细胞中上调。在 AR KO 小鼠中，SCI 导致的损伤病变面积比 WT 小鼠小。AR 缺失诱导的小胶质细胞/巨噬细胞诱导 M2 反应而不是 M1 反应，并促进 SCI 后小鼠的运动恢复。在体外实验中，小胶质细胞系 (N9 或 BV2) 用 AR 抑制剂 (ARI) fidarestat 处理。AR 抑制导致 4-羟基壬烯醛 (HNE) 积累，从而诱导 cAMP 反应元件结合蛋白 (CREB) 的磷酸化以促进 Arg1 表达。磷酸化 CREB 的特异性抑制剂 KG501 可以取消 ARI 或 HNE 刺激引起的 Arg1 上调。我们的结果表明，AR 作为一种开关，根据其活性状态，通过将细胞极化到 M1 或 M2 表型来调节小胶质细胞，从而可以调节小胶质细胞。我们建议抑制 AR 可能是未来 SCI 的一种有前途的治疗方法。
