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首页> 外文期刊>Journal of neuroinflammation >PD-L1 enhances CNS inflammation and infarct volume following experimental stroke in mice in opposition to PD-1
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PD-L1 enhances CNS inflammation and infarct volume following experimental stroke in mice in opposition to PD-1

机译：PD-L1增强了小鼠中风后与PD-1相反的中枢神经系统炎症和梗死体积

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Background Stroke severity is worsened by recruitment of inflammatory immune cells into the brain. This process depends in part on T cell activation, in which the B7 family of co-stimulatory molecules plays a pivotal role. Previous studies demonstrated more severe infarcts in mice lacking programmed death-1 (PD-1), a member of the B7 family, thus implicating PD-1 as a key factor in limiting stroke severity. The purpose of this study was to determine if this protective effect of PD-1 involves either of its ligands, PD-L1 or PD-L2. Methods Central nervous system (CNS) inflammation and infarct volume were evaluated in male PD-L1 and PD-L2 knockout (-/-) mice undergoing 60 minutes of middle cerebral artery occlusion (MCAO) followed by 96 hours of reperfusion and compared to wild-type (WT) C57BL/6J mice. Results PD-L1-/- and PD-L2-/- mice had smaller total infarct volumes compared to WT mice. The PD-L1-/- and to a lesser extent PD-L2-/- mice had reduced levels of proinflammatory activated microglia and/or infiltrating monocytes and CD4+ T cells in the ischemic hemispheres. There was a reduction in ischemia-related splenic atrophy accompanied by lower activation status of splenic T cells and monocytes in the absence of PD-L1, suggesting a pathogenic rather than a regulatory role for both PD-1 ligands (PD-Ls). Suppressor T cells (IL-10-producing CD8+CD122+ T cells) trafficked to the brain in PD-L1-/- mice and there was decreased expression of CD80 on splenic antigen-presenting cells (APCs) as compared to the WT and PD-L2-/- mice. Conclusions Our novel observations are the first to implicate PD-L1 involvement in worsening outcome of experimental stroke. The presence of suppressor T cells in the right MCAO-inflicted hemisphere in mice lacking PD-L1 implicates these cells as possible key contributors for controlling adverse effects of ischemia. Increased expression of CD80 on APCs in WT and PD-L2-/- mice suggests an overriding interaction leading to T cell activation. Conversely, low CD80 expression by APCs, along with increased PD-1 and PD-L2 expression in PD-L1-/- mice suggests alternative T cell signaling pathways, leading to a suppressor phenotype. These results suggest that agents (for example antibodies) that can target and neutralize PD-L1/2 may have therapeutic potential for treatment of human stroke.
机译：背景通过将炎性免疫细胞募集到大脑中使中风的严重性恶化。这个过程部分取决于T细胞活化，其中B7家族的共刺激分子起着关键作用。先前的研究表明，缺乏编程性死亡1（PD-1）（B7家族的一员）的小鼠中的梗塞更为严重，因此暗示PD-1是限制卒中严重程度的关键因素。这项研究的目的是确定PD-1的这种保护作用是否涉及其配体PD-L1或PD-L2。方法对雄性PD-L1和PD-L2基因敲除（-/-）小鼠进行60分钟大脑中动脉闭塞（MCAO），然后再灌注96小时，并与野生动物进行比较，评估其中枢神经系统炎症和梗死体积型（WT）C57BL / 6J小鼠。结果与WT小鼠相比，PD-L1-/-和PD-L2-/-小鼠具有较小的总梗塞体积。 PD-L1-/-和程度较小的PD-L2-/-小鼠在缺血性半球中促炎性小胶质细胞和/或浸润的单核细胞和CD4 + T细胞水平降低。在不存在PD-L1的情况下，缺血相关的脾萎缩有所减少，同时脾T细胞和单核细胞的活化状态降低，表明这两种PD-1配体（PD-Ls）均具有致病性而非调节作用。与WT和PD相比，PD-L1-/-小鼠中抑制性T细胞（产生IL-10的CD8 + CD122 + T细胞）迁移到大脑，并且CD80在脾抗原呈递细胞（APC）上的表达降低。 -L2-/-小鼠。结论我们的新发现是第一个暗示PD-L1参与使实验性中风恶化的研究。在缺乏PD-L1的小鼠中，右MCAO损伤的半球中存在抑制性T细胞，暗示这些细胞可能是控制缺血不良反应的关键因素。 WT和PD-L2-/-小鼠在APC上CD80的表达增加表明，相互作用占主导，导致T细胞活化。相反，APC的CD80低表达以及PD-L1-/-小鼠中PD-1和PD-L2表达的增加提示了替代性T细胞信号传导途径，导致了抑制型。这些结果表明，可以靶向和中和PD-L1 / 2的试剂（例如抗体）可能具有治疗人类中风的治疗潜力。

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