Roles of programmed death protein 1/programmed death-ligand 1 in secondary brain injury after intracerebral hemorrhage in rats: selective modulation of microglia polarization to anti-inflammatory phenotype.
Roles of programmed death protein 1/programmed death-ligand 1 in secondary brain injury after intracerebral hemorrhage in rats: selective modulation of microglia polarization to anti-inflammatory phenotype.
复制标题
DOI：
10.1186/s12974-017-0790-0
复制
发表时间：
2017-02-14
影响因子：
9.3
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Wu J;Sun L;Li H;Shen H;Zhai W;Yu Z;Chen G
小胶质细胞及其分化在脑内血肿继发性脑损伤中起着重要作用。已报道程序性死亡蛋白1/程序性死亡配体1调节神经免疫细胞功能。信号转导子和转录激活子1参与小胶质细胞的极化，程序性死亡蛋白1/程序性死亡配体1可调节信号转导子和转录激活子1的激活。在此，我们显示了程序性死亡蛋白1/程序性死亡配体1在大鼠模型脑内血肿诱导的继发性脑损伤过程中小胶质细胞极化中的关键作用。在Sprague道利大鼠（体重250-300 g）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模拟脑出血。程序性死亡蛋白1和程序性死亡配体1的特异性siRNA和pDNA在体内和体外都被利用。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，以及信号转导子和转录激活子1的磷酸化水平均高于假手术组，并在脑出血后24 h达到峰值。程序性死亡蛋白1和程序性死亡配体1的过表达改善了脑内血肿诱导的继发性脑损伤，包括脑细胞死亡，神经元变性和炎症，而它们的敲除则诱导了相反的效果。此外，脑出血后程序性死亡蛋白1和程序性死亡配体1的过表达选择性地促进小胶质细胞向抗炎表型的极化，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的增加可能是一种自助。增强程序性死亡蛋白1和程序性死亡配体1的表达可能诱导选择性调节小胶质细胞极化为抗炎表型，用于脑出血治疗。
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.