Abstract

Proteoglycans (PGs) are one of the main components in the extracellular matrix of the central nervous system. Chondroitin sulfate (CS) is a glycosaminoglycan (GAG), which is composed of major PGs. Similar to keratin sulfate (KS), another GAG, CS inhibits axon regeneration. However, the influence of these GAGs on the pathogenicity of neuroimmunological diseases is unclear. Here, we induced experimental autoimmune encephalomyelitis (EAE) in mice lacking CS N-acetylgalactosaminyltransferase-1 (CSGalNAcT1-KO), an important enzyme for CS synthesis. In our study, CSGalNAcT1-KO mice showed milder EAE symptoms than those in wild-type (WT) mice. The recall response of antigen-specific lymphocytes showed that CSGalNAcT1-KO-derived lymphocytes had a milder cell proliferation response than that in WT-derived lymphocytes. These results suggest that CS contributes toward the induction phase of EAE. We previously performed EAE experiments in GlcNAc-6-O-sulfotransferase KO (GlcNAc6ST-KO) and C6ST1-KO mice, which had reduced KS and reduced CS-C, respectively. EAE in CSGalNAcT1-KO mice was more similar to that in GlcNAc6ST-KO mice than in C6ST1-KO mice. In conclusion, the distinct GAG sugar chains are associated with severe or mild phenotypes of EAE and are therefore potential new therapeutic targets for neuroimmunological diseases, including multiple sclerosis.

中文翻译：

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硫酸软骨素 N-乙酰半乳糖基转移酶 1 敲除在实验性自身免疫性脑脊髓炎中显示出比野生型更温和的表型

摘要

蛋白聚糖（PGs）是中枢神经系统细胞外基质的主要成分之一。硫酸软骨素 (CS) 是一种糖胺聚糖 (GAG)，由主要的 PG 组成。与另一种 GAG 硫酸角蛋白 (KS) 类似，CS 抑制轴突再生。然而，这些GAGs对神经免疫疾病致病性的影响尚不清楚。在这里，我们在缺乏 CS N-乙酰半乳糖胺基转移酶-1 (CSGalNAcT1-KO)（CS 合成的重要酶）的小鼠中诱导了实验性自身免疫性脑脊髓炎 (EAE)。在我们的研究中，CSGalNAcT1-KO 小鼠表现出比野生型 (WT) 小鼠更轻微的 EAE 症状。抗原特异性淋巴细胞的回忆反应表明，CSGalNAcT1-KO 衍生的淋巴细胞比 WT 衍生的淋巴细胞具有更温和的细胞增殖反应。这些结果表明CS有助于EAE的诱导阶段。我们之前在 GlcNAc-6-O-磺基转移酶 KO (GlcNAc6ST-KO) 和 C6ST1-KO 小鼠中进行了 EAE 实验，它们分别降低了 KS 和降低了 CS-C。CSGalNAcT1-KO 小鼠中的 EAE 与 GlcNAc6ST-KO 小鼠中的 EAE 比 C6ST1-KO 小鼠中的更相似。总之，不同的 GAG 糖链与 EAE 的严重或轻度表型相关，因此是包括多发性硬化症在内的神经免疫疾病的潜在新治疗靶点。