NO Mediates Microglial Response to Acute Spinal Cord Injury Under ATP Control In Vivo
NO Mediates Microglial Response to Acute Spinal Cord Injury Under ATP Control In Vivo
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DOI：
10.1002/glia.20993
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发表时间：
2010-07-01
期刊：
影响因子：
6.2
通讯作者：
Kirchhoff, Frank
中科院分区：
文献类型：
--
作者：
Dibaj, Payam;Nadrigny, Fabien;Kirchhoff, Frank
了解脊髓损伤的病理机制是发展有效治疗方法的前提。通过研究急性损伤的脊髓白色物质在麻醉小鼠与荧光标记的小胶质细胞和轴突在体内双光子激光扫描显微镜（2 P-LSM），我们确定了信使一氧化氮（NO）作为一个调制器的损伤激活的小胶质细胞。高功率激光脉冲引起的局部组织损伤引起小胶质细胞突起的立即吸引。脊髓灌流NO合酶和鸟苷酸环化酶抑制剂阻断了这些扩展。此外，局部注射NO供体精胺NONOate（SPNO）或NO依赖性第二信使cGMP诱导小胶质细胞向注射部位有效迁移。高组织水平的NO，通过均匀灌注SPNO和模仿延长组织损伤，导致小胶质细胞形状从分枝到阿米巴样的快速转换，表明细胞活化。当脊髓白色物质预处理的增加，周围的ATP（称为小胶质细胞趋化因子）水平，吸引小胶质细胞的过程中，局部NO释放增强，而它被取消在低水平的组织ATP。由于两种信号分子NO和ATP介导急性小胶质细胞反应，因此协调NO和嘌呤能通路的药理学靶向将是影响脊髓损伤后先天免疫过程的有效手段。(C)2010 Wiley-Liss，Inc.
To understand the pathomechanisms of spinal cord injuries will be a prerequisite to develop efficient therapies. By investigating acute lesions of spinal cord white matter in anesthetized mice with fluorescently labeled microglia and axons using in vivo two-photon laser-scanning microscopy (2P-LSM), we identified the messenger nitric oxide (NO) as a modulator of injury-activated microglia. Local tissue damages evoked by high-power laser pulses provoked an immediate attraction of microglial processes. Spinal superfusion with NO synthase and guanylate cyclase inhibitors blocked these extensions. Furthermore, local injection of the NO-donor spermine NONOate (SPNO) or the NO-dependent second messenger cGMP induced efficient migration of microglial cells toward the injection site. High-tissue levels of NO, achieved by uniform superfusion with SPNO and mimicking extended tissue damage, resulted in a fast conversion of the microglial shape from ramified to ameboid indicating cellular activation. When the spinal white matter was preconditioned by increased, ambient ATP (known as a microglial chemoattractant) levels, the attraction of microglial processes to local NO release was augmented, whereas it was abolished at low levels of tissue ATP. Because both signaling molecules, NO and ATP, mediate acute microglial reactions, coordinated pharmacological targeting of NO and purinergic pathways will be an effective mean to influence the innate immune processes after spinal cord injury. (C) 2010 Wiley-Liss, Inc.