4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis.
4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis.
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4-乙基鸟醇调节神经炎症和Th1/Th17在实验性自身免疫性脑脊髓炎中改善疾病严重程度的分化。
DOI：
10.1186/s12974-021-02143-w
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发表时间：
2021-05-11
影响因子：
9.3
通讯作者：
Yen JH
中科院分区：
文献类型：
--
作者：
Weng WT;Kuo PC;Brown DA;Scofield BA;Furnas D;Paraiso HC;Wang PY;Yu IC;Yen JH
多发性硬化症 (MS) 是一种进行性自身免疫性疾病，其特征是致病性炎症免疫细胞在中枢神经系统 (CNS) 中积聚，随后导致局灶性炎症、脱髓鞘、轴突损伤和神经元损伤。实验性自身免疫性脑脊髓炎 (EAE) 是一种完善的小鼠模型，可模拟多发性硬化症的主要特征。目前，据报道，饮食中食用富含酚类的食物具有许多健康益处，包括抗炎活性。一种这样的化合物，4-乙基愈创木酚 (4-EG)，存在于各种食物中，已知可以减弱炎症免疫反应。然而，4-EG是否在调节中枢神经系统炎症免疫反应方面发挥抗炎作用仍不清楚。因此，在本研究中，我们使用慢性和复发缓解动物模型评估了 4-EG 在 EAE 中的治疗效果，并研究了 4-EG 对 EAE 中神经炎症和 Th1/Th17 分化的免疫调节作用。诱导慢性 C57BL/6 EAE 和复发缓解型 SJL/J EAE，然后进行 4-EG 治疗。评估了 4-EG 对 EAE 疾病进展、外周 Th1/Th17 分化、CNS Th1/Th17 浸润、小胶质细胞 (MG) 激活和血脑屏障 (BBB) 破坏的影响。此外，还评估了 C57BL/6 EAE 小鼠 CNS 中 MMP9、MMP3、HO-1 和 Nrf2 的表达。我们的结果表明，4-EG 不仅可以改善 C57BL/6 慢性 EAE 的疾病严重程度，还可以减轻 SJL/J 复发缓解型 EAE 的疾病进展。对细胞和分子机制的进一步研究表明，4-EG 可抑制 MG 激活，减轻 BBB 破坏，抑制 MMP3/MMP9 产生，并抑制 EAE 中枢神经系统中 Th1 和 Th17 的浸润。此外，4-EG 抑制 EAE 周围以及体外 Th1 和 Th17 培养物中的 Th1 和 Th17 分化。最后，我们发现4-EG在体内EAE的CNS以及体外MG、BV2细胞和巨噬细胞中诱导HO-1表达。我们的工作表明，4-EG 通过调节神经炎症和抑制 Th1 和 Th17 分化来提供针对自身免疫性疾病 EAE 的保护，这表明 4-EG 作为一种天然化合物，有可能开发为治疗 MS/EAE 的治疗剂。在线版本包含可在 10.1186/s12974-021-02143-w 获取的补充材料。
Multiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, axonal injury, and neuronal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model that mimics the key features of MS. Presently, the dietary consumption of foods rich in phenols has been reported to offer numerous health benefits, including anti-inflammatory activity. One such compound, 4-ethylguaiacol (4-EG), found in various foods, is known to attenuate inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unknown. Thus, in this study, we assessed the therapeutic effect of 4-EG in EAE using both chronic and relapsing-remitting animal models and investigated the immunomodulatory effects of 4-EG on neuroinflammation and Th1/Th17 differentiation in EAE. Chronic C57BL/6 EAE and relapsing-remitting SJL/J EAE were induced followed by 4-EG treatment. The effects of 4-EG on disease progression, peripheral Th1/Th17 differentiation, CNS Th1/Th17 infiltration, microglia (MG) activation, and blood-brain barrier (BBB) disruption in EAE were evaluated. In addition, the expression of MMP9, MMP3, HO-1, and Nrf2 was assessed in the CNS of C57BL/6 EAE mice. Our results showed that 4-EG not only ameliorated disease severity in C57BL/6 chronic EAE but also mitigated disease progression in SJL/J relapsing-remitting EAE. Further investigations of the cellular and molecular mechanisms revealed that 4-EG suppressed MG activation, mitigated BBB disruption, repressed MMP3/MMP9 production, and inhibited Th1 and Th17 infiltration in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE and in vitro Th1 and Th17 cultures. Finally, we found 4-EG induced HO-1 expression in the CNS of EAE in vivo as well as in MG, BV2 cells, and macrophages in vitro. Our work demonstrates that 4-EG confers protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1 and Th17 differentiation, suggesting 4-EG, a natural compound, could be potentially developed as a therapeutic agent for the treatment of MS/EAE. The online version contains supplementary material available at 10.1186/s12974-021-02143-w.
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影响因子：
7.3
作者：
Greter M;Lelios I;Croxford AL
通讯作者：
Croxford AL
影响因子：
32.4
作者：
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影响因子：
2.4
作者：
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