Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
Int J Mol Sci. 2021 Apr 27;22(9):4574. doi: 10.3390/ijms22094574.
In multiple sclerosis (MS), oligodendrocyte precursor cells (OPCs) are recruited to the site of injury to remyelinate damaged axons; however, in patients this process is often ineffective due to defects in OPC maturation. The membrane receptor GPR17 timely regulates the early stages of OPC differentiation; however, after reaching its highest levels in immature oligodendrocytes, it has to be downregulated to allow terminal maturation. Since, in several animal models of disease GPR17 is upregulated, the aim of this work was to characterize GPR17 alterations in MS patients. We developed immunohistochemistry and immunofluorescence procedures for the detection of GPR17 in human tissues and stained post-mortem MS brain lesions from patients with secondary progressive MS and control subjects. The inflammatory activity in each lesion was evaluated by immunohistochemistry for the myelin protein MOG and the HLA antigen to classify them as active, chronic inactive or chronic active. Hence, we assessed the distribution of GPR17-positive cells in these lesions compared to normal appearing white matter (NAWM) and white matter (WM) of control subjects. Our data have shown a marked increase of GPR17-expressing oligodendroglial cells accumulating at NAWM, in which moderate inflammation was also found. Furthermore, we identified two distinct subpopulations of GPR17-expressing oligodendroglial cells, characterized by either ramified or rounded morphology, that differently populate the WM of healthy controls and MS patients. We concluded that the coordinated presence of GPR17 in OPCs at the lesion sites and inflamed NAWM areas suggests that GPR17 could be exploited to support endogenous remyelination through advanced pharmacological approaches.
在多发性硬化症（MS）中，少突胶质前体细胞（OPC）被募集到损伤部位以修复受损的轴突；然而，在患者中，由于 OPC 成熟缺陷，该过程通常无效。膜受体 GPR17 及时调节 OPC 分化的早期阶段；然而，在未成熟的少突胶质细胞中达到最高水平后，它必须下调以允许终末成熟。由于在几种疾病动物模型中 GPR17 上调，本工作的目的是表征 MS 患者中 GPR17 的改变。我们开发了用于检测人类组织中 GPR17 的免疫组织化学和免疫荧光程序，并对继发进展性 MS 患者和对照受试者的 MS 脑损伤进行了染色。通过髓鞘蛋白 MOG 和 HLA 抗原的免疫组织化学评估每个病变的炎症活性，将其分类为活跃、慢性非活跃或慢性活跃。因此，我们评估了与正常外观白质（NAWM）和对照受试者 WM 相比，这些病变中 GPR17 阳性细胞的分布。我们的数据显示，在 NAWM 处积累的表达 GPR17 的少突胶质细胞明显增加，其中也发现中度炎症。此外，我们鉴定了两种不同形态的表达 GPR17 的少突胶质细胞亚群，它们分别以分支或圆形形态存在，不同地分布在健康对照者和 MS 患者的 WM 中。我们得出结论，GPR17 在病变部位和炎症性 NAWM 区域的 OPC 中的协调存在表明，GPR17 可以通过先进的药理方法来支持内源性髓鞘再生。
