Zujovic V, Benavides J, Vigé X, Carter C, Taupin V
Sanofi-Synthélabo, CNS Research Department, Bagneux, France.
Glia. 2000 Feb 15;29(4):305-15.
Among the chemokine family, fractalkine shows unusual properties: it exists as a membrane-bound and soluble protein, and both fractalkine and its receptor CX(3)CR1 are expressed predominantly in the central nervous system. In rat cell culture models, the chemokine fractalkine was expressed in neurons and microglia, but not in astrocytes and its receptor exclusively localized to microglial cells, where its expression was downregulated by treatment with the bacterial endotoxin (LPS). In microglial cultures, LPS (10 ng/ml) induced a marked increase in the release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). The effects of LPS on TNF-alpha secretion were partially blocked (30%) by fractalkine and the effects of fractalkine were reversed by a polyclonal anti-fractalkine antibody. When microglial-associated fractalkine was neutralized by anti-fractalkine antibody, the LPS response was increased by 80%, suggesting tonic activation of microglial fractalkine receptors by endogenous fractalkine. The effects of the antibody were antagonized by the addition of fractalkine. LPS-activated microglia were neurotoxic when added to neuronal hippocampal culture, producing 20% neuronal death, as measured by NeuN-positive cell counting. An anti-fractalkine antibody produced neurotoxic effects of similar magnitude in this co-culture system and also markedly potentiated the neurotoxic effects of LPS-activated microglia (40% neuronal death). These results suggest that endogenous fractalkine might act tonically as an anti-inflammatory chemokine in cerebral tissue through its ability to control and suppress certain aspects of microglial activation. These data may have relevance to degenerative conditions such as multiple sclerosis, in which cerebral inflammatory processes may be activated.
在趋化因子家族中，fractalkine具有不同寻常的特性：它以膜结合蛋白和可溶性蛋白的形式存在，且fractalkine及其受体CX(3)CR1主要在中枢神经系统中表达。在大鼠细胞培养模型中，趋化因子fractalkine在神经元和小胶质细胞中表达，但在星形胶质细胞中不表达，其受体仅定位于小胶质细胞，在小胶质细胞中其表达可被细菌内毒素（LPS）处理下调。在小胶质细胞培养物中，LPS（10 ng/ml）可诱导促炎细胞因子肿瘤坏死因子-α（TNF-α）释放显著增加。fractalkine可部分阻断（30%）LPS对TNF-α分泌的作用，而多克隆抗fractalkine抗体可逆转fractalkine的作用。当抗fractalkine抗体中和小胶质细胞相关的fractalkine时，LPS反应增加80%，提示内源性fractalkine对小胶质细胞fractalkine受体有持续激活作用。添加fractalkine可拮抗该抗体的作用。将LPS激活的小胶质细胞加入神经元海马培养物中时具有神经毒性，通过NeuN阳性细胞计数测量，可导致20%的神经元死亡。在该共培养系统中，抗fractalkine抗体产生了类似程度的神经毒性作用，并且还显著增强了LPS激活的小胶质细胞的神经毒性作用（40%的神经元死亡）。这些结果表明，内源性fractalkine可能通过其控制和抑制小胶质细胞激活某些方面的能力，在脑组织中作为一种抗炎趋化因子发挥持续作用。这些数据可能与诸如多发性硬化症等退行性疾病相关，在这些疾病中脑部炎症过程可能被激活。
