Trypanosoma brucei Secreted Aromatic Ketoacids Activate the Nrf2/HO-1 Pathway and Suppress Pro-inflammatory Responses in Primary Murine Glia and Macrophages
Trypanosoma brucei Secreted Aromatic Ketoacids Activate the Nrf2/HO-1 Pathway and Suppress Pro-inflammatory Responses in Primary Murine Glia and Macrophages
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DOI：
10.3389/fimmu.2019.02137
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发表时间：
2019-09-11
影响因子：
7.3
通讯作者：
Dunne, Aisling
中科院分区：
文献类型：
--
作者：
Campbell, Nicole K.;Williams, David G.;Dunne, Aisling
非洲锥虫，如布氏锥虫(T.brucei)，是哺乳动物血管和中枢神经系统的原生动物寄生虫，最为人所知的是导致人类致命的昏睡病。作为唯一的胞外寄生虫，锥虫不断受到宿主免疫防御的挑战，但它们已经开发出非常有效的策略来逃避和调节这些反应，以保持感染，同时延长宿主的生存时间。在这里，我们研究宿主寄生虫的相互作用，特别是在中枢神经系统的背景下，这一点还没有被很好地理解。我们证明布鲁氏毛滴虫在体外强烈上调原代小鼠神经胶质细胞和巨噬细胞中的应激反应蛋白--血红素加氧酶1(HO-1)。此外，利用一种新的AHADH(In)布氏毛滴虫细胞系，我们证明了布鲁氏毛虫血液中分泌的特定芳香酮酸是HO-1表达的有效驱动因素，并能够抑制胶质细胞和巨噬细胞中前IL-1β的诱导。此外，我们还发现，这些酮酸显著减少了神经胶质细胞产生IL-6和肿瘤坏死因子α，但对巨噬细胞没有影响。最后，我们提出的数据支持Nrf2激活作为这些酮酸上调HO-1表达和调节其抗炎活性的作用机制。因此，本研究报道了一种新的免疫逃避机制，即布鲁氏毛滴虫通过分泌氨基酸衍生的代谢物来抑制宿主中枢和外周免疫反应，可能是通过诱导Nrf2/HO-1途径实现的。
African trypanosomes, such as Trypanosoma brucei (T. brucei), are protozoan parasites of the mammalian vasculature and central nervous system that are best known for causing fatal human sleeping sickness. As exclusively extracellular parasites, trypanosomes are subject to constant challenge from host immune defenses but they have developed very effective strategies to evade and modulate these responses to maintain an infection while simultaneously prolonging host survival. Here we investigate host parasite interactions, especially within the CNS context, which are not well-understood. We demonstrate that T. brucei strongly upregulates the stress response protein, Heme Oxygenase 1 (HO-1), in primary murine glia and macrophages in vitro. Furthermore, using a novel AHADH(in) T. brucei cell line, we demonstrate that specific aromatic ketoacids secreted by bloodstream forms of T. brucei are potent drivers of HO-1 expression and are capable of inhibiting pro-IL1 beta induction in both glia and macrophages. Additionally, we found that these ketoacids significantly reduced IL-6 and TNF a production by glia, but not macrophages. Finally, we present data to support Nrf2 activation as the mechanism of action by which these ketoacids upregulate HO-1 expression and mediate their anti-inflammatory activity. This study therefore reports a novel immune evasion mechanism, whereby T. brucei secretes amino-acid derived metabolites for the purpose of suppressing both the host CNS and peripheral immune response, potentially via induction of the Nrf2/HO-1 pathway.