Dimethyl itaconate, an itaconate derivative, exhibits immunomodulatory effects on neuroinflammation in experimental autoimmune encephalomyelitis
Dimethyl itaconate, an itaconate derivative, exhibits immunomodulatory effects on neuroinflammation in experimental autoimmune encephalomyelitis
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DOI：
10.1186/s12974-020-01768-7
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发表时间：
2020-04-29
影响因子：
9.3
通讯作者：
Yen, Jui-Hung
中科院分区：
文献类型：
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作者：
Kuo, Ping-Chang;Weng, Wen-Tsan;Yen, Jui-Hung
炎症刺激诱导免疫应答基因1（IRG 1）表达，IRG 1反过来催化三羧酸循环中衣康酸的产生。衣康酸最近已成为免疫细胞功能的调节剂，特别是在巨噬细胞中。研究表明，在小鼠和人巨噬细胞中，LPS激活抗炎转录因子Nrf 2需要衣康酸，缺乏内源性衣康酸产生的LPS激活的IRG 1（-/-）巨噬细胞表现出增强的炎症反应。此外，衣康酸二甲酯（衣康酸酯衍生物）抑制角质形成细胞中IL-17诱导的I κ B σ活化，并调节银屑病动物模型中IL-17-I κ B σ途径介导的皮肤炎症。目前，衣康酸盐对调节巨噬细胞功能和外周炎性免疫应答的作用已得到充分证实。然而，其对小胶质细胞（MG）和CNS炎症免疫反应的影响仍有待研究。因此，我们研究衣康酸是否具有免疫调节作用，调节MG激活和中枢神经系统炎症的动物模型多发性硬化症，实验性自身免疫性脑脊髓炎（EAE）。方法采用C57 BL/6小鼠慢性EAE模型，给予地塞米松治疗。测定了雷公藤多甙对EAE疾病严重程度、血脑屏障（BBB）破坏、MG活化、外周Th 1/Th 17分化和Th 1/Th 17细胞CNS浸润的影响。原代培养MG以研究雷公藤多甙对MG活化的影响。采用复发缓解型SJL/J EAE模型评价雷公藤多甙的疗效。结果在慢性C57 BL/6 EAE模型中，我们的研究结果表明，在慢性C57 BL/6 EAE模型中，地塞米松改善了疾病的严重程度。进一步的细胞和分子机制分析显示，雷公藤多甙减轻BBB破坏，抑制MMP 3/MMP 9的产生，抑制小胶质细胞活化，抑制外周Th 1/Th 17分化，抑制Th 1和Th 17细胞的CNS浸润。引人注目的是，在复发缓解型SJL/J EAE模型中，EAE还表现出减轻复发严重程度的治疗效果。结论本研究表明，EAE患者的神经系统炎症反应和疾病严重程度可通过多种细胞和分子机制得到改善，提示EAE可通过其免疫调节和抗炎作用成为治疗MS/EAE的新药物。
Background Inflammatory stimuli induce immunoresponsive gene 1 (IRG1) expression that in turn catalyzes the production of itaconate from the tricarboxylic acid cycle. Itaconate has recently emerged as a regulator of immune cell functions, especially in macrophages. Studies show that itaconate is required for the activation of anti-inflammatory transcription factor Nrf2 by LPS in mouse and human macrophages, and LPS-activated IRG1(-/-) macrophages that lack endogenous itaconate production exhibit augmented inflammatory responses. Moreover, dimethyl itaconate (DMI), an itaconate derivative, inhibits IL-17-induced I kappa B sigma activation in keratinocytes and modulates IL-17-I kappa B sigma pathway-mediated skin inflammation in an animal model of psoriasis. Currently, the effect of itaconate on regulating macrophage functions and peripheral inflammatory immune responses is well established. However, its effect on microglia (MG) and CNS inflammatory immune responses remains unexplored. Thus, we investigated whether itaconate possesses an immunomodulatory effect on regulating MG activation and CNS inflammation in animal models of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Methods Chronic C57BL/6 EAE was induced followed by DMI treatment. The effect of DMI on disease severity, blood-brain barrier (BBB) disruption, MG activation, peripheral Th1/Th17 differentiation, and the CNS infiltration of Th1/Th17 cells in EAE was determined. Primary MG was cultured to study the effect of DMI on MG activation. Relapsing-remitting SJL/J EAE was induced to assess the therapeutic effect of DMI. Results Our results show DMI ameliorated disease severity in the chronic C57BL/6 EAE model. Further analysis of the cellular and molecular mechanisms revealed that DMI mitigated BBB disruption, inhibited MMP3/MMP9 production, suppressed microglia activation, inhibited peripheral Th1/Th17 differentiation, and repressed the CNS infiltration of Th1 and Th17 cells. Strikingly, DMI also exhibited a therapeutic effect on alleviating severity of relapse in the relapsing-remitting SJL/J EAE model. Conclusions We demonstrate that DMI suppresses neuroinflammation and ameliorates disease severity in EAE through multiple cellular and molecular mechanisms, suggesting that DMI can be developed as a novel therapeutic agent for the treatment of MS/EAE through its immunomodulatory and anti-inflammatory properties.