Abstract
BackgroundMicroglia 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.MethodsAn 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.ResultsIn 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.ConclusionsEnhancing 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.
Highlights
Microglia and its polarization play critical roles in intracerebral hemorrhage-induced secondary brain injury
The results showed that there were no significant differences between the vector group and Programmed death-1 (PD-1) plasmid group or programmed death-ligand 1 (PD-L1) plasmid group, while there were significant differences between the control small interfering RNA (siRNA) group and PD-1 siRNA group or PD-L1 siRNA group, suggesting that PD-1 and PD-L1complement each other in modulation of brain cell death and neuronal degeneration in Intracerebral hemorrhage (ICH) rats
The results showed that ICH mainly selectively modulated microglia polarizing to pro-inflammatory phenotype, which was ameliorated by overexpression of PD-1 and PD-L1 and aggravated by knockdown of PD-1 and PD-L1
Summary
Microglia and its polarization play critical roles in intracerebral hemorrhage-induced secondary brain injury. 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 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. Recent reports have shown that microglia/macrophages are the main regulatory cells in the immune defense response of the central nervous system (CNS) that affect subsequent inflammatory processes [10, 11]. Numerous recent studies have shown that in response to brain injury, different phenotypes of microglia/macrophages are observed and play various roles based on signals released in the microenvironment [11, 13]. Microglia activation and polarization during experimental intracerebral hemorrhage has been reported [14, 15]
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