Neutrophil Enzyme Myeloperoxidase Modulates Neuronal Response in a Model of Subarachnoid Hemorrhage by Venous Injury.
Neutrophil Enzyme Myeloperoxidase Modulates Neuronal Response in a Model of Subarachnoid Hemorrhage by Venous Injury.
复制标题
DOI：
10.1161/strokeaha.120.033513
复制
发表时间：
2021-10
期刊：
影响因子：
8.3
通讯作者：
Provencio JJ
中科院分区：
文献类型：
--
作者：
Coulibaly AP;Pezuk P;Varghese P;Gartman W;Triebwasser D;Kulas JA;Liu L;Syed M;Tvrdik P;Ferris H;Provencio JJ
动脉瘤性蛛网膜下腔出血（SAH）与迟发性认知缺陷的发生有关。中性粒细胞浸润中枢神经系统 (CNS) 与 SAH 后这些缺陷的发生有关。然而，尚不清楚中性粒细胞活性如何影响SAH中的中枢神经系统功能。本项目旨在阐明哪些中性粒细胞因子介导蛛网膜下腔出血后中枢神经系统损伤和认知缺陷。使用 SAH 小鼠模型和中性粒细胞效应功能缺陷的小鼠，我们确定了哪种中性粒细胞效应功能对于 SAH 后缺陷的发展至关重要。采用体内和体外技术研究 SAH 后中性粒细胞影响的可能途径。我们的结果表明，缺乏功能性髓过氧化物酶（MPO）（一种中性粒细胞酶）的小鼠既缺乏脑膜中性粒细胞浸润（WT，假872细胞/脑膜与SAH 3047，p=0.023；MPOKO，假1677与SAH 1636，p=NS），又消除了与SAH相关的巴恩斯迷宫认知缺陷（MPOKO）假手术与 SAH，p=NS）。在出血时将具有生物活性的 MPO 及其底物过氧化氢 (H2O2) 重新引入 MPOKO 小鼠的脑脊液中，可恢复 SAH 后观察到的空间记忆缺陷（到达目标框的时间 MPOKO 假手术与 MPOKO+MPO/H2O2，p=0.001）。我们发现 MPO/H2O2 使神经元、星形胶质细胞和小胶质细胞发生变化的证据表明 MPO 的作用可能与许多细胞类型具有复杂的相互作用。暴露于 MPO/H2O2 的神经元在基线和氯化钾刺激后显示出钙活性降低。尽管星形胶质细胞和小胶质细胞受到影响，但星形胶质细胞中观察到的变化与可能影响神经元的炎症变化最为一致。这些结果表明 MPO 通过影响神经元和神经胶质细胞而成为 SAH 神经元功能障碍的介质。这些结果表明，在蛛网膜下腔出血中，脑膜中先天免疫细胞的活性调节底层脑组织的活性和功能。
Aneurysmal subarachnoid hemorrhage (SAH) is associated with the development of delayed cognitive deficits. Neutrophil infiltration into the central nervous system (CNS) is linked to the development of these deficits after SAH. It is however unclear how neutrophil activity influences CNS function in SAH. The present project aims to elucidate which neutrophil factors mediate CNS injury and cognitive deficits after SAH. Using a murine model of SAH and mice deficient in neutrophil effector functions, we determined which neutrophil effector function is critical to the development of deficits after SAH. In vivo and in vitro techniques were used to investigate possible pathways of neutrophils effect after SAH. Our results show that mice lacking functional myeloperoxidase (MPO), a neutrophil enzyme, lack both the meningeal neutrophil infiltration (WT, sham 872 cells/meninges vs. SAH 3047, p=0.023; MPOKO, sham 1677 vs. SAH 1636, p=NS) and erase the cognitive deficits on Barnes maze associated with SAH (MPOKO sham vs. SAH, p=NS). The re-introduction of biologically active MPO, and its substrate hydrogen peroxide (H2O2), to the cerebrospinal fluid of MPOKO mice at the time of hemorrhage restores the spatial memory deficit observed after SAH (time to goal box MPOKO sham vs. MPOKO+MPO/H2O2, p=0.001). We find evidence of changes in neurons, astrocytes and microglia with MPO/H2O2 suggesting the effect of MPO may have complex interactions with many cell types. Neurons exposed to MPO/H2O2 show decreased calcium activity at baseline and after stimulation with potassium chloride. Although astrocytes and microglia are affected, changes seen in astrocytes are most consistent with inflammatory changes that likely affect neurons. These results implicate MPO as a mediator of neuronal dysfunction in SAH through its effect on both neurons and glia. These results show that, in SAH, the activity of innate immune cells in the meninges modulates the activity and function of the underlying brain tissue.