Hypoxia-inducible factor 1α modulates metabolic activity and cytokine release in anti-Aspergillus fumigatus immune responses initiated by human dendritic cells
Hypoxia-inducible factor 1α modulates metabolic activity and cytokine release in anti-Aspergillus fumigatus immune responses initiated by human dendritic cells
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DOI：
10.1016/j.ijmm.2015.08.036
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发表时间：
2015-12-01
影响因子：
4.1
通讯作者：
Loeffler, Juergen
中科院分区：
文献类型：
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作者：
Fliesser, Mirjam;Morton, Charles Oliver;Loeffler, Juergen
霉菌烟曲霉会对免疫功能低下的患者造成危及生命的感染。在过去的十年中，新的研究发现提高了我们对烟曲霉宿主相互作用的理解，包括最近鉴定出骨髓表达的缺氧诱导因子 1 α (HIF-1 α) 作为相关的免疫调节转录因子和抗真菌防御的潜在治疗靶点。然而，HIF-1 α 信号传导对于人类抗 A 的功能。人们对烟菌免疫的了解仍然知之甚少，包括它在树突状细胞 (DC) 中的作用，而树突状细胞是抗真菌免疫的重要调节因子。本研究调查了 HIF-1 α 在抗 A 抗体中的功能相关性。由人类 DC 发起的烟曲霉免疫反应。包括缺氧细胞培养条件，因为烟曲霉感染期间会出现缺氧微环境，并可能影响宿主免疫反应。在常氧和缺氧条件下用烟曲霉刺激后，HIF-1 α 在 DC 中稳定。这种稳定性部分依赖于 dectin-1，它是人类 DC 上烟曲霉的主要受体。使用基于 siRNA 的 HIF-1 α 沉默结合全基因组转录分析，确定了 HIF-1 α 对人类 DC 抗真菌免疫反应的调节作用。具体而言，HIF-1α沉默和非沉默DC的转录组的差异表明，在常氧和缺氧条件下，HIF-1α有助于DC代谢和响应烟曲霉的细胞因子释放。进一步的下游分析证实了这一点，包括代谢物分析和时程感染实验的细胞因子分析。因此，这项研究揭示了迄今为止尚未描述的 HIF-1 α 在人类 DC 对烟曲霉反应中的功能相关性。 (C) 2015 爱思唯尔有限公司。版权所有。
The mold Aspergillus fumigatus causes life-threatening infections in immunocompromised patients. Over the past decade, new findings in research have improved our understanding of A. fumigatus host interactions, including the recent identification of myeloid-expressed hypoxia-inducible factor 1 alpha (HIF-1 alpha) as a relevant immune-modulating transcription factor and potential therapeutic target in anti-fungal defense. However, the function of HIF-1 alpha signaling for human anti-A. fumigatus immunity is still poorly understood, including its role in dendritic cells (DCs), which are important regulators of anti-fungal immunity. This study investigated the functional relevance of HIF-1 alpha in the anti-A. fumigatus immune response initiated by human DCs. Hypoxic cell culture conditions were included because hypoxic microenvironments occur during A. fumigatus infections and may influence the host immune response. HIF-1 alpha was stabilized in DCs following stimulation with A. fumigatus under normoxic and hypoxic conditions. This stabilization was partially dependent on dectin-1, the major receptor for A. fumigatus on human DCs. Using siRNA-based HIF-1 alpha silencing combined with genome-wide transcriptional analysis, a modulatory effect of HIF-1 alpha on the anti-fungal immune response of human DCs was identified. Specifically, the difference in the transcriptomes of HIF-1 alpha silenced and non-silenced DCs indicated that HIF-1 alpha contributes to DC metabolism and cytokine release in response to A. fumigatus under normoxic as well as hypoxic conditions. This was confirmed by further down-stream analyses that included metabolite analysis and cytokine profiling of a time-course infection experiment. Thereby, this study revealed a so far undescribed functional relevance of HIF-1 alpha in human DC responses against A. fumigatus. (C) 2015 Elsevier GmbH. All rights reserved.