Fernandez Ana M, Fernandez Silvia, Carrero Paloma, Garcia-Garcia Miguel, Torres-Aleman Ignacio
Laboratory of Neuroendocrinology, Cajal Institute, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
J Neurosci. 2007 Aug 15;27(33):8745-56. doi: 10.1523/JNEUROSCI.1002-07.2007.
Maladaptive inflammation is a major suspect in progressive neurodegeneration, but the underlying mechanisms are difficult to envisage in part because reactive glial cells at lesion sites secrete both proinflammatory and anti-inflammatory mediators. We now report that astrocytes modulate neuronal resilience to inflammatory insults through the phosphatase calcineurin. In quiescent astrocytes, inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) recruits calcineurin to stimulate a canonical inflammatory pathway involving the transcription factors nuclear factor kappaB (NFkappaB) and nuclear factor of activated T-cells (NFAT). However, in reactive astrocytes, local anti-inflammatory mediators such as insulin-like growth factor I also recruit calcineurin but, in this case, to inhibit NFkappaB/NFAT. Proof of concept experiments in vitro showed that expression of constitutively active calcineurin in astrocytes abrogated the inflammatory response after TNF-alpha or endotoxins and markedly enhanced neuronal survival. Furthermore, regulated expression of constitutively active calcineurin in astrocytes markedly reduced inflammatory injury in transgenic mice, in a calcineurin-dependent manner. These results suggest that calcineurin forms part of a molecular pathway whereby reactive astrocytes determine the outcome of the neuroinflammatory process by directing it toward either its resolution or its progression.
适应性炎症是进行性神经退行性变的主要可疑因素，但其潜在机制难以设想，部分原因是损伤部位的反应性胶质细胞会分泌促炎和抗炎介质。我们现在报告，星形胶质细胞通过磷酸酶钙调神经磷酸酶调节神经元对炎症损伤的恢复力。在静止的星形胶质细胞中，肿瘤坏死因子-α（TNF-α）等炎症介质会募集钙调神经磷酸酶，以刺激涉及转录因子核因子κB（NFκB）和活化T细胞核因子（NFAT）的经典炎症途径。然而，在反应性星形胶质细胞中，胰岛素样生长因子I等局部抗炎介质也会募集钙调神经磷酸酶，但在这种情况下，是为了抑制NFκB/NFAT。体外概念验证实验表明，星形胶质细胞中组成型活性钙调神经磷酸酶的表达消除了TNF-α或内毒素后的炎症反应，并显著提高了神经元的存活率。此外，星形胶质细胞中组成型活性钙调神经磷酸酶的调控表达以钙调神经磷酸酶依赖的方式显著减少了转基因小鼠的炎症损伤。这些结果表明，钙调神经磷酸酶构成了分子途径的一部分，通过该途径，反应性星形胶质细胞通过将神经炎症过程导向其消退或进展来决定神经炎症过程的结果。
