Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune encephalomyelitis
Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune encephalomyelitis
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DOI：
10.1073/pnas.0915112107
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发表时间：
2010-07-06
影响因子：
11.1
通讯作者：
Narumiya, Shuh
中科院分区：
文献类型：
--
作者：
Esaki, Yoshiyasu;Li, Youxian;Narumiya, Shuh
实验性自身免疫性脑脊髓炎（EAE）是多发性硬化症（MS）的动物模型。尽管MS患者脑脊液中前列腺素（PG）浓度升高，但PG在MS中的作用尚不清楚。我们通过对每种PG受体类型或亚型缺陷的小鼠进行EAE诱导，并使用对四种PGE受体（EP）亚型中的每一种都有选择性的激动剂或拮抗剂来研究这个问题。在PG受体缺陷小鼠中，只有EP 4（-/-）小鼠表现出对EAE的显著抑制，这在野生型小鼠中模拟，并且在更大程度上在EP 2（-/-）小鼠中通过在免疫阶段施用EP 4拮抗剂ONO-AE 3 -208来模拟。免疫过程中的EP 4拮抗作用也抑制了野生型小鼠中抗原特异性辅助性T细胞（Th）1和Th 17细胞的产生，并在更大程度上抑制了EP 2（-/-）小鼠的产生。在EAE发作时给予ONO-AE-3208对疾病严重程度几乎没有影响，并且在整个实验期间给予它没有引起疾病峰值的显著降低，这表明，除了在免疫阶段的促进作用之外，EP 4在诱发阶段发挥预防作用。在EAE发作时给予EP 4激动剂ONO-AE 1 -329延迟和抑制疾病进展，并抑制血脑屏障通透性的相关增加。因此，PGE（2）在EAE中发挥双重功能，在免疫过程中通过EP 4和EP 2促进Th 1和Th 17细胞冗余生成，并通过EP 4保护血脑屏障来减弱这些细胞侵入脑。
Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). Although prostaglandin (PG) concentrations are increased in cerebrospinal fluid of MS patients, the role of PGs in MS is unknown. We examined this issue by subjecting mice deficient in each PG receptor type or subtype to EAE induction and using agonists or antagonists selective for each of the four PGE receptor (EP) subtypes. Among PG receptor-deficient mice, only EP4(-/-) mice manifested significant suppression of EAE, which was mimicked in wild-type mice and to a greater extent, in EP2(-/-) mice by administration of the EP4 antagonist ONO-AE3-208 during the immunization phase. EP4 antagonism during immunization also suppressed the generation of antigen-specific T helper (Th) 1 and Th17 cells in wild-type mice and to a greater extent, in EP2(-/-) mice. ONO-AE-3208 administration at EAE onset had little effect on disease severity, and its administration throughout the experimental period did not cause significant reduction of the peak of disease, suggesting that, in addition to its facilitative action during the immunization phase, EP4 exerts a preventive action in the elicitation phase. Administration of the EP4 agonist ONO-AE1-329 at EAE onset delayed and suppressed disease progression as well as inhibited the associated increase in permeability of the blood-brain barrier. Thus, PGE(2) exerts dual functions in EAE, facilitating Th1 and Th17 cell generation redundantly through EP4 and EP2 during immunization and attenuating invasion of these cells into the brain by protecting the blood -brain barrier through EP4.