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 IκBς activation in keratinocytes and modulates IL-17-IκBς 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.

中文翻译：

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衣康酸酯的二甲基衣康酸酯衍生物，在实验性自身免疫性脑脊髓炎中表现出对神经炎症的免疫调节作用。

背景技术炎性刺激诱导免疫应答基因1（IRG1）表达，进而催化三羧酸循环中衣康酸酯的产生。衣康酸酯最近已成为免疫细胞功能的调节剂，特别是在巨噬细胞中。研究表明衣康酸是小鼠和人类巨噬细胞中LPS激活抗炎转录因子Nrf2所必需的，而缺乏内源衣康酸产生的LPS激活的IRG1-/-巨噬细胞表现出增强的炎症反应。此外，在牛皮癣的动物模型中，衣康酸酯的二甲基衣康酸酯（DMI）抑制IL-17诱导的角质形成细胞中的IκBς活化并调节IL-17-IκBς途径介导的皮肤炎症。目前，衣康酸酯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）和中枢神经系统炎性免疫反应的影响尚待探索。因此，我们调查了衣康酸酯在多发性硬化症，实验性自身免疫性脑脊髓炎（EAE）动物模型中是否具有调节MG激活和中枢神经系统炎症的免疫调节作用。方法诱导慢性C57BL / 6 EAE，然后进行DMI治疗。确定了DMI对疾病严重程度，血脑屏障（BBB）破坏，MG激活，外周Th1 / Th17分化以及EAE中Th1 / Th17细胞的CNS浸润的影响。培养原代MG以研究DMI对MG激活的影响。诱导复发缓解型SJL / J EAE以评估DMI的治疗效果。结果我们的结果表明，在慢性C57BL / 6 EAE模型中，DMI改善了疾病严重程度。细胞和分子机制的进一步分析表明，DMI减轻了BBB的破坏，抑制了MMP3 / MMP9的产生，抑制了小胶质细胞的活化，抑制了外周Th1 / Th17的分化，并抑制了CNS对Th1和Th17细胞的浸润。令人惊讶的是，DMI在缓解复发的SJL / J EAE模型中也显示出对减轻复发严重程度的治疗作用。结论我们证明DMI可通过多种细胞和分子机制抑制EAE中的神经炎症并改善疾病严重程度，这表明DMI可通过其免疫调节和抗炎特性发展成为治疗MS / EAE的新型治疗剂。