Polarization of Microglia to the M2 Phenotype in a Peroxisome Proliferator-Activated Receptor Gamma-Dependent Manner Attenuates Axonal Injury Induced by Traumatic Brain Injury in Mice
Polarization of Microglia to the M2 Phenotype in a Peroxisome Proliferator-Activated Receptor Gamma-Dependent Manner Attenuates Axonal Injury Induced by Traumatic Brain Injury in Mice
复制标题
小胶质细胞以 PPAR-γ 依赖性方式极化至 M2 表型可减轻小鼠脑外伤引起的轴突损伤
DOI：
10.1089/neu.2017.5540
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发表时间：
2018-06-07
影响因子：
4.2
通讯作者：
Yang, Xiaofeng
中科院分区：
文献类型：
--
作者：
Wen, Liang;You, Wendong;Yang, Xiaofeng
越来越多的证据表明，激活的小胶质细胞在创伤性脑损伤后的炎症反应中起重要作用。抑制M1和刺激M2激活的小胶质细胞在几种中枢神经系统疾病的动物模型中显示出保护作用。然而，目前尚不清楚小胶质细胞对M2的极化是否减轻了脑外伤后的轴突损伤。在本研究中，我们使用了一种侧向液压冲击损伤装置来诱导小鼠轴突损伤。将小鼠随机分为假手术组、脑损伤组、脑损伤+罗格列酮(PPAR-γ激动剂)组和脑损伤+GW9662(PPAR-γ拮抗剂)组。用β-淀粉样前体蛋白免疫组织化学染色评价轴突损伤。用酶联免疫吸附试验评价炎症反应，用M1和M2小胶质细胞特异性标志物评价小胶质细胞极化，用神经功能严重程度评分评价神经功能。脑外伤后，M1表型的小胶质细胞明显增多，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极化到M2表型，从而减轻炎症反应，减轻大脑皮层轴突损伤，改善神经功能。相反，GW9662抑制小胶质细胞对M2的极化，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研究结果与我们在体内的实验结果一致。综上所述，小胶质细胞通过激活PPAR-γ向M2表型极化可减轻小鼠脑损伤后的轴突损伤，这可能是治疗脑创伤后轴突损伤的潜在途径。
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-gamma] agonist), and TBI + GW9662 (PPAR-gamma 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-gamma 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-gamma activation attenuated axonal injury following TBI in mice, which may be a potential therapeutic approach for TBI-induced axonal injury.