Hypoxia-inducible factor 1α modulates metabolic activity and cytokine release in anti-Aspergillus fumigatus immune responses initiated by human dendritic cells.

Abstract

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 1α (HIF-1α) as a relevant immune-modulating transcription factor and potential therapeutic target in anti-fungal defense. However, the function of HIF-1α 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-1α 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-1α 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-1α silencing combined with genome-wide transcriptional analysis, a modulatory effect of HIF-1α on the anti-fungal immune response of human DCs was identified. Specifically, the difference in the transcriptomes of HIF-1α silenced and non-silenced DCs indicated that HIF-1α 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-1α in human DC responses against A. fumigatus.

• Authors: Mirjam Fliesser, Charles Oliver Morton, Michael Bonin, Frank Ebel, Kerstin Hünniger, Oliver Kurzai, Hermann Einsele, Jürgen Löffler
• Journal: International journal of medical microbiology : IJMM (Int J Med Microbiol) Vol. 305 Issue 8 Pg. 865-73 (Dec 2015) ISSN: 1618-0607 [Electronic] Germany
• PMID: 26387061 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier GmbH. All rights reserved.

Chemical References

• Cytokines
• Hypoxia-Inducible Factor 1, alpha Subunit

Topics

• Aspergillus fumigatus (immunology)
• Cell Hypoxia
• Cells, Cultured
• Cytokines (metabolism)
• Dendritic Cells (immunology, microbiology)
• Gene Expression Profiling
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)