INSERM UMR-S1124, Toxicologie Pharmacologie et Signalisation cellulaire, Paris, France.
Université Paris Descartes, 45 rue des Saints-Pères, 75006, Paris, France.
Sci Rep. 2017 Aug 29;7(1):9794. doi: 10.1038/s41598-017-09621-3.
The Aryl hydrocarbon Receptor(AhR) is among the most important receptors which bind pollutants; however it also regulates signaling pathways independently of such exposure. We previously demonstrated that AhR is expressed during development of the central nervous system(CNS) and that its deletion leads to the occurrence of a congenital nystagmus. Objectives of the present study are to decipher the origin of these deficits, and to identify the role of the AhR in the development of the CNS. We show that the AhR-knockout phenotype develops during early infancy together with deficits in visual-information-processing which are associated with an altered optic nerve myelin sheath, which exhibits modifications in its lipid composition and in the expression of myelin-associated-glycoprotein(MAG), a cell adhesion molecule involved in myelin-maintenance and glia-axon interaction. In addition, we show that the expression of pro-inflammatory cytokines is increased in the impaired optic nerve and confirm that inflammation is causally related with an AhR-dependent decreased expression of MAG. Overall, our findings demonstrate the role of the AhR as a physiological regulator of myelination and inflammatory processes in the developing CNS. It identifies a mechanism by which environmental pollutants might influence CNS myelination and suggest AhR as a relevant drug target for demyelinating diseases.
芳香烃受体（AhR）是结合污染物的最重要受体之一；然而，它也可以独立于这种暴露来调节信号通路。我们之前证明，AhR 在中枢神经系统（CNS）发育过程中表达，其缺失会导致先天性眼球震颤的发生。本研究的目的是破译这些缺陷的起源，并确定 AhR 在 CNS 发育中的作用。我们表明，AhR 敲除表型在婴儿早期与视觉信息处理缺陷一起发展，这与视神经髓鞘的改变有关，其脂质组成和髓鞘相关糖蛋白（MAG）的表达发生改变，MAG 是一种参与髓鞘维持和胶质细胞-轴突相互作用的细胞粘附分子。此外，我们还表明，受损视神经中的促炎细胞因子表达增加，并证实炎症与 AhR 依赖性 MAG 表达减少有关。总的来说，我们的研究结果表明，AhR 作为生理调节剂在发育中的 CNS 中的髓鞘形成和炎症过程中发挥作用。它确定了环境污染物可能影响 CNS 髓鞘形成的机制，并表明 AhR 是脱髓鞘疾病的一个相关药物靶点。
