PD-L1 enhances CNS inflammation and infarct volume following experimental stroke in mice in opposition to PD-1.
PD-L1 enhances CNS inflammation and infarct volume following experimental stroke in mice in opposition to PD-1.
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DOI：
10.1186/1742-2094-10-111
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发表时间：
2013-09-09
影响因子：
9.3
通讯作者：
Offner H
中科院分区：
文献类型：
--
作者：
Bodhankar S;Chen Y;Vandenbark AA;Murphy SJ;Offner H
中风的严重程度因炎症免疫细胞进入大脑而恶化。这个过程部分依赖于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，缺乏程序性死亡-1（PD-1）（B7家族成员）的小鼠发生更严重的梗死，因此暗示PD-1是限制中风严重程度的关键因素。本研究的目的是确定PD-1的这种保护作用是否涉及其配体PD-L1或PD-L2。在经历60分钟大脑中动脉闭塞（MCAO）随后96小时再灌注的雄性PD-L1和PD-L2敲除（-/-）小鼠中评价中枢神经系统（CNS）炎症和梗死体积，并与野生型（WT）C57 BL/6 J小鼠进行比较。与WT小鼠相比，PD-L1-/-和PD-L2-/-小鼠的总梗死体积较小。PD-L1-/-和PD-L2-/-小鼠在缺血半球中的促炎活化小胶质细胞和/或浸润单核细胞和CD 4 + T细胞水平降低，程度较轻。在不存在PD-L1的情况下，缺血相关的脾萎缩减少，伴有脾T细胞和单核细胞的较低活化状态，表明两种PD-1配体（PD-L）的致病作用而不是调节作用。与WT和PD-L2-/-小鼠相比，PD-L1-/-小鼠中的抑制性T细胞（产生IL-10的CD 8 + CD 122 + T细胞）运输至脑，脾抗原呈递细胞（APC）上的CD 80表达降低。我们的新观察首次暗示PD-L1参与实验性卒中的恶化结局。在缺乏PD-L1的小鼠中，MCAO造成的右半球中存在抑制性T细胞，这表明这些细胞可能是控制缺血不良反应的关键因素。WT和PD-L2-/-小鼠中APC上CD 80的表达增加表明导致T细胞活化的压倒性相互作用。相反，APC的低CD 80表达，沿着PD-L1-/-小鼠中PD-1和PD-L2表达的增加，提示替代的T细胞信号传导途径，导致抑制表型。这些结果表明，可以靶向和中和PD-L1/2的药剂（例如抗体）可能具有治疗人类中风的治疗潜力。
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. 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. 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. 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.
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影响因子：
168.9
作者：
Castillo, J;Davalos, A;Noya, M
通讯作者：
Noya, M
影响因子：
5.3
作者：
McColl, Barry W.;Rothwell, Nancy J.;Allan, Stuart M.
通讯作者：
Allan, Stuart M.
影响因子：
8.3
作者：
Gelderblom, Mathias;Leypoldt, Frank;Magnus, Tim
通讯作者：
Magnus, Tim
DOI：
10.1016/j.jstrokecerebrovasdis.2004.07.004
发表时间：
2004-09-01
期刊：
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association
影响因子：
--
作者：
Elkind, Mitchell S V;Cheng, Jianfeng;Sacco, Ralph L
通讯作者：
Sacco, Ralph L
影响因子：
4.4
作者：
Offner, Halina;Subramanian, Sandhya;Hurn, Patricia D.
通讯作者：
Hurn, Patricia D.