1 Department of Neurosurgery, First Affiliated Hospital, College of Medicine, Zhejiang University , Hangzhou, Zhejiang Province, China .
2 Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China .
J Neurotrauma. 2018 Oct 1;35(19):2330-2340. doi: 10.1089/neu.2017.5540. Epub 2018 Jun 7.
Increasing evidence indicates that activated microglia play an important role in the inflammatory response following traumatic brain injury (TBI). Inhibiting M1 and stimulating M2 activated microglia have demonstrated protective effects in several animal models of central nervous system diseases. However, it is not clear whether the polarization of microglia to M2 attenuates axonal injury following TBI. In this study, we used a lateral fluid percussion injury device to induce axonal injury in mice. Mice were randomly assigned to the sham, TBI, TBI + rosiglitazone (peroxisome proliferator-activated receptor gamma [PPAR-γ] agonist), and TBI + GW9662 (PPAR-γ antagonist) groups. Axonal injury was assessed using immunohistochemical staining for beta amyloid precursor protein. The inflammatory response was assessed by enzyme-linked immunosorbent assay, microglia polarization was assessed using specific markers of M1 and M2 microglia, and neurological function was assessed using the neurological severity score. Following TBI, microglia of the M1 phenotype increased significantly, while those of the M2 phenotype decreased. Rosiglitazone-induced PPAR-γ activation promoted microglia polarization to the M2 phenotype, which reduced the inflammatory response, attenuated axonal injury in the cerebral cortex, and improved neurological function. Conversely, GW9662 inhibited the polarization of microglia to M2 and aggravated inflammation and axonal injury. Our in vitro findings in lipopolysaccharide-induced microglia were consistent with those of our in vivo experiments. In conclusion, the polarization of microglia to the M2 phenotype via PPAR-γ activation attenuated axonal injury following TBI in mice, which may be a potential therapeutic approach for TBI-induced axonal injury.
越来越多的证据表明，激活的小胶质细胞在创伤性脑损伤（TBI）后的炎症反应中发挥重要作用。在几种中枢神经系统疾病的动物模型中，抑制 M1 并刺激 M2 激活的小胶质细胞已显示出保护作用。然而，小胶质细胞向 M2 极化是否减轻 TBI 后的轴突损伤尚不清楚。在这项研究中，我们使用侧脑室液压冲击装置诱导小鼠发生轴突损伤。将小鼠随机分为假手术组、TBI 组、TBI+罗格列酮（过氧化物酶体增殖物激活受体γ [PPAR-γ] 激动剂）组和 TBI+GW9662（PPAR-γ 拮抗剂）组。通过β淀粉样前体蛋白免疫组织化学染色评估轴突损伤。通过酶联免疫吸附试验评估炎症反应，通过 M1 和 M2 小胶质细胞的特异性标志物评估小胶质细胞极化，通过神经功能严重程度评分评估神经功能。TBI 后，M1 表型的小胶质细胞显著增加，而 M2 表型的小胶质细胞减少。罗格列酮诱导的 PPAR-γ 激活促进小胶质细胞向 M2 表型极化，从而减少炎症反应，减轻大脑皮质的轴突损伤，并改善神经功能。相反，GW9662 抑制小胶质细胞向 M2 的极化，并加重炎症和轴突损伤。我们在脂多糖诱导的小胶质细胞中的体外发现与我们的体内实验结果一致。总之，通过 PPAR-γ 激活使小胶质细胞向 M2 表型极化减轻了小鼠 TBI 后的轴突损伤，这可能是 TBI 诱导的轴突损伤的一种潜在治疗方法。
