Expression of functionally distinct ecto-5′-nucleotidase/CD73 glycovariants in reactive astrocytes in experimental autoimmune encephalomyelitis and neuroinflammatory conditions in vitro,Glia

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Expression of functionally distinct ecto-5′-nucleotidase/CD73 glycovariants in reactive astrocytes in experimental autoimmune encephalomyelitis and neuroinflammatory conditions in vitro
Glia ( IF 5.4 ) Pub Date : 2023-08-30 , DOI: 10.1002/glia.24459
Marija Adzic Bukvic ₁ , Danijela Laketa ₁ , Milorad Dragic ₁ , Irena Lavrnja ₂ , Nadezda Nedeljkovic ₁

Affiliation

Ecto-5′-nucleotidase/CD73 (eN/CD73) is a membrane-bound enzyme involved in extracellular production of adenosine and a cell adhesion molecule involved in cell–cell interactions. In neuroinflammatory conditions such as experimental autoimmune encephalomyelitis (EAE), reactive astrocytes occupying active demyelination areas significantly upregulate eN/CD73 and express additional eN/CD73 variants. The present study investigated whether the different eN/CD73 variants represent distinct glycoforms and the functional consequences of their expression in neuroinflammatory states. The study was performed in animals at different stages of EAE and in primary astrocyte cultures treated with a range of inflammatory cytokines. Upregulation at the mRNA, protein, and functional levels, as well as the appearance of multiple eN/CD73 glycovariants were detected in the inflamed spinal cord tissue. At the peak of the disease, eN/CD73 exhibited higher AMP turnover and lower enzyme-substrate affinity than the control group, which was attributed to altered glycosylation under neuroinflammatory conditions. A subsequent in vitro study showed that primary astrocytes upregulated eN/CD73 and expressed the multiple glycovariants upon stimulation with TNFα, IL-1β, IL-6, and ATP, with the effect occurring at least in part via induction of JAK/STAT3 signaling. Experimental removal of glycan moieties from membrane glycoproteins by PNGaseF decreased eN/CD73 activity but had no effect on the enzyme's involvement in astrocyte migration. Our results suggest that neuroinflammatory states are associated with the appearance of functionally distinct eN/CD73 glycovariants, which may play a role in the development of the reactive astrocyte phenotype.

中文翻译：

体外实验性自身免疫性脑脊髓炎和神经炎症条件下反应性星形胶质细胞中功能不同的 5′-核苷酸酶/CD73 糖变体的表达

Ecto-5'-核苷酸酶/CD73 (eN/CD73) 是一种膜结合酶，参与细胞外腺苷的产生，也是参与细胞间相互作用的细胞粘附分子。在实验性自身免疫性脑脊髓炎 (EAE) 等神经炎症性疾病中，占据活跃脱髓鞘区域的反应性星形胶质细胞显着上调 eN/CD73 并表达额外的 eN/CD73 变体。本研究调查了不同的 eN/CD73 变体是否代表不同的糖型以及它们在神经炎症状态下表达的功能后果。该研究是在处于 EAE 不同阶段的动物和用一系列炎症细胞因子处理的原代星形胶质细胞培养物中进行的。在发炎的脊髓组织中检测到 mRNA、蛋白质和功能水平的上调以及多种 eN/CD73 糖变体的出现。在疾病高峰期，eN/CD73 表现出比对照组更高的 AMP 周转率和更低的酶底物亲和力，这归因于神经炎症条件下糖基化的改变。随后的体外研究表明，在 TNFα、IL-1β、IL-6 和 ATP 刺激下，原代星形胶质细胞上调 eN/CD73 并表达多种糖变体，该效应至少部分通过诱导 JAK/STAT3 信号传导而发生。通过 PNGaseF 从膜糖蛋白中去除聚糖部分的实验降低了 eN/CD73 活性，但对该酶参与星形胶质细胞迁移没有影响。我们的结果表明，神经炎症状态与功能不同的 eN/CD73 糖变体的出现有关，这可能在反应性星形胶质细胞表型的发展中发挥作用。

更新日期：2023-08-30

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