Wu Jie, Sun Liang, Li Haiying, Shen Haitao, Zhai Weiwei, Yu Zhengquan, Chen Gang
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province, 215006, China.
J Neuroinflammation. 2017 Feb 14;14(1):36. doi: 10.1186/s12974-017-0790-0.
Microglia and its polarization play critical roles in intracerebral hemorrhage-induced secondary brain injury. Programmed death protein 1/programmed death-ligand 1 has been reported to regulate neuroimmune cell functions. Signal transducers and activators of transcription 1 participate in microglia polarization, and programmed death protein 1/programmed death-ligand 1 could regulate the activation of signal transducers and activators of transcription 1. We herein show the critical role of programmed death protein 1/programmed death-ligand 1 in the polarization of microglia during intracerebral hemorrhage-induced secondary brain injury in rat models.
An autologous blood intracerebral hemorrhage model was established in Sprague Dawley rats (weighing 250-300 g), and primary cultured microglia was exposed to oxyhemoglobin to mimic intracerebral hemorrhage in vitro. Specific siRNAs and pDNA for programmed death protein 1 and programmed death-ligand 1 were exploited both in vivo and in vitro.
In the brain tissue around hematoma, the protein levels of programmed death protein 1 and programmed death-ligand 1 and the interaction between them, as well as the phosphorylation of signal transducers and activators of transcription 1, were higher than that of the sham group and collectively peaked at 24 h after intracerebral hemorrhage. Overexpression of programmed death protein 1 and programmed death-ligand 1 ameliorated intracerebral hemorrhage-induced secondary brain injury, including brain cell death, neuronal degeneration, and inflammation, while their knockdown induced an opposite effect. In addition, overexpression of programmed death protein 1 and programmed death-ligand 1 selectively promoted microglia polarization to anti-inflammation phenotype after intracerebral hemorrhage and inhibited the phosphorylation of signal transducers and activators of transcription 1, suggesting that intracerebral hemorrhage-induced increases in programmed death protein 1 and programmed death-ligand 1 maybe a self-help.
Enhancing the expressions of programmed death protein 1 and programmed death-ligand 1 may induce a selective modulation of microglia polarization to anti-inflammation phenotype for intracerebral hemorrhage treatment.
小胶质细胞及其极化在脑出血诱导的继发性脑损伤中起关键作用。据报道，程序性死亡蛋白1/程序性死亡配体1可调节神经免疫细胞功能。信号转导和转录激活因子1参与小胶质细胞极化，程序性死亡蛋白1/程序性死亡配体1可调节信号转导和转录激活因子1的激活。我们在此展示了程序性死亡蛋白1/程序性死亡配体1在大鼠脑出血诱导的继发性脑损伤中对小胶质细胞极化的关键作用。
在体重250 - 300 g的Sprague Dawley大鼠中建立自体血脑出血模型，并将原代培养的小胶质细胞暴露于氧合血红蛋白以在体外模拟脑出血。在体内和体外均使用针对程序性死亡蛋白1和程序性死亡配体1的特异性小干扰RNA和质粒DNA。
在血肿周围脑组织中，程序性死亡蛋白1和程序性死亡配体1的蛋白水平及其相互作用，以及信号转导和转录激活因子1的磷酸化水平均高于假手术组，并在脑出血后24小时集体达到峰值。程序性死亡蛋白1和程序性死亡配体1的过表达改善了脑出血诱导的继发性脑损伤，包括脑细胞死亡、神经元变性和炎症，而它们的敲低则产生相反的效果。此外，程序性死亡蛋白1和程序性死亡配体1的过表达在脑出血后选择性促进小胶质细胞向抗炎表型极化，并抑制信号转导和转录激活因子1的磷酸化，提示脑出血诱导的程序性死亡蛋白1和程序性死亡配体1增加可能是一种自我保护机制。
增强程序性死亡蛋白1和程序性死亡配体1的表达可能诱导小胶质细胞选择性地向抗炎表型极化，从而用于脑出血治疗。
