Departamento de Neurociencias, Universidad del País Vasco-UPV/EHU, Barrio Sarriena s/n, 48940, Leioa, Spain, Achucarro Basque Center for Neuroscience-UPV/EHU, 48170, Zamudio, Spain, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940, Leioa, Spain.
Glia. 2014 Feb;62(2):171-84. doi: 10.1002/glia.22596. Epub 2013 Nov 19.
Microglia, the resident immune cells of the central nervous system, responds to brain disarrangements by becoming activated to contend with brain damage. Here we show that the expression of P2X4 receptors is upregulated in inflammatory foci and in activated microglia in the spinal cord of rats with experimental autoimmune encephalomyelitis (EAE) as well as in the optic nerve of multiple sclerosis patients. To study the role of P2X4 receptors in microgliosis, we activated microglia with LPS in vitro and in vivo. We observed that P2X4 receptor activity in vitro was increased in LPS-activated microglia as assessed by patch-clamp recordings. In addition, P2X4 receptor blockade significantly reduced microglial membrane ruffling, TNFα secretion and morphological changes, as well as LPS-induced microglial cell death. Accordingly, neuroinflammation provoked by LPS injection in vivo induced a rapid microglial loss in the spinal cord that was totally prevented or potentiated by P2X4 receptor blockade or facilitation, respectively. Within the brain, microglia in the hippocampal dentate gyrus showed particular vulnerability to LPS-induced neuroinflammation. Thus, microglia processes in this region retracted as early as 2 h after injection of LPS and died around 24 h later, two features which were prevented by blocking P2X4 receptors. Together, these data suggest that P2X4 receptors contribute to controlling the fate of activated microglia and its survival.
小胶质细胞是中枢神经系统的固有免疫细胞，在对脑紊乱做出反应时会被激活，以应对脑损伤。在这里，我们表明，在实验性自身免疫性脑脊髓炎（EAE）大鼠脊髓的炎症灶和激活的小胶质细胞以及多发性硬化症患者的视神经中，P2X4 受体的表达上调。为了研究 P2X4 受体在小胶质细胞增生中的作用，我们在体外和体内用 LPS 激活小胶质细胞。我们观察到，通过膜片钳记录评估，体外 LPS 激活的小胶质细胞中 P2X4 受体活性增加。此外，P2X4 受体阻断显著减少了小胶质细胞的膜皱襞、TNFα 分泌和形态变化，以及 LPS 诱导的小胶质细胞死亡。因此，体内 LPS 注射引起的神经炎症在脊髓中迅速引起小胶质细胞丢失，这种丢失可分别通过 P2X4 受体阻断或促进完全预防或增强。在大脑中，海马齿状回的小胶质细胞对 LPS 诱导的神经炎症特别敏感。因此，该区域的小胶质细胞突起在注射 LPS 后 2 小时内就开始回缩，大约 24 小时后死亡，这些特征可通过阻断 P2X4 受体来预防。综上所述，这些数据表明 P2X4 受体有助于控制激活的小胶质细胞的命运及其存活。
