Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization
Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization
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DOI：
10.1073/pnas.1525086113
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发表时间：
2016-02-02
影响因子：
11.1
通讯作者：
Bollyky, Paul L.
中科院分区：
文献类型：
--
作者：
Kuipers, Hedwich F.;Rieck, Mary;Bollyky, Paul L.
细胞外基质多糖透明质酸 (HA) 在自身免疫性炎症部位积聚，包括多发性硬化症 (MS) 中的白质病变，但其在发病机制中的功能重要性尚不清楚。我们评估了 4-甲基伞形酮 (4-MU)（一种口服 HA 合成抑制剂）对多发性硬化症实验性自身免疫性脑脊髓炎 (EAE) 小鼠模型疾病进展的影响。 4-MU 治疗可降低 EAE 的发生率、延迟其发作并减轻已确定疾病的严重程度。 4-MU 抑制自身反应性 T 细胞的激活并防止其极化为 Th1 表型。相反，4-MU 促进向 Th2 表型极化并诱导 Foxp3(+) 调节性 T 细胞。此外，4-MU 加速 T 细胞通过次级淋巴器官的运输，损害 T 细胞对 CNS 实质的浸润，并限制星形胶质细胞增生。总之，这些数据表明 HA 合成对于 EAE 疾病进展是必要的，并且 4-MU 治疗可能是 CNS 自身免疫的潜在治疗策略。考虑到 4-MU 已经是一种名为 Hymecromone 的治疗药物，被批准用于治疗人类胆道痉挛，我们建议将其重新用于治疗多发性硬化症。
The extracellular matrix polysaccharide hyaluronan (HA) accumulates at sites of autoimmune inflammation, including white matter lesions in multiple sclerosis (MS), but its functional importance in pathogenesis is unclear. We have evaluated the impact of 4-methylumbelliferone (4-MU), an oral inhibitor of HA synthesis, on disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Treatment with 4-MU decreases the incidence of EAE, delays its onset, and reduces the severity of established disease. 4-MU inhibits the activation of autoreactive T cells and prevents their polarization toward a Th1 phenotype. Instead, 4-MU promotes polarization toward a Th2 phenotpye and induction of Foxp3(+) regulatory T cells. Further, 4-MU hastens trafficking of T cells through secondary lymphoid organs, impairs the infiltration of T cells into the CNS parenchyma, and limits astrogliosis. Together, these data suggest that HA synthesis is necessary for disease progression in EAE and that treatment with 4-MU may be a potential therapeutic strategy in CNS autoimmunity. Considering that 4-MU is already a therapeutic, called hymecromone, that is approved to treat biliary spasm in humans, we propose that it could be repurposed to treat MS.