Desferrioxamine Supports Metabolic Function in Primary Human Macrophages Infected With Mycobacterium tuberculosis
| Autor: | Sharee A. Basdeo, Joseph Keane, Mary P. O'Sullivan, Simone Christa Tazoll, Karl M. Gogan, Cilian Ó Maoldomhnaigh, Kate McQuaid, Colin Kenny, Seónadh O'Leary, Donal J. Cox, Luke A. J. O'Neill, Maureen J. O'Sullivan, James J. Phelan |
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| Rok vydání: | 2020 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
0301 basic medicine Tuberculosis immunometabolism Immunology Microbiology Mycobacterium tuberculosis 03 medical and health sciences 0302 clinical medicine Immune system medicine Immunology and Allergy Macrophage iron metabolism Glycolysis iron chelation Innate immune system biology glycolysis biology.organism_classification medicine.disease Warburg effect 030104 developmental biology tuberculosis Anaerobic glycolysis lcsh:RC581-607 030215 immunology |
| Zdroj: | Frontiers in Immunology, Vol 11 (2020) |
| ISSN: | 1664-3224 |
| DOI: | 10.3389/fimmu.2020.00836 |
| Popis: | Tuberculosis is the single biggest infectious killer in the world and presents a major global health challenge. Antimicrobial therapy requires many months of multiple drugs and incidences of drug resistant tuberculosis continues to rise. Consequently, research is now focused on the development of therapies to support the function of infected immune cells. HIF1α-mediated induction of aerobic glycolysis is integral to the host macrophage response during infection with Mtb, as this promotes bacillary clearance. Some iron chelators have been shown to modulate cellular metabolism through the regulation of HIF1α. We examined if the iron chelator, desferrioxamine (DFX), could support the function of primary human macrophages infected with Mtb. Using RT-PCR, we found that DFX promoted the expression of key glycolytic enzymes in Mtb-infected primary human MDMs and human alveolar macrophages. Using Seahorse technology, we demonstrate that DFX enhances glycolytic metabolism in Mtb-stimulated human MDMs, while helping to enhance glycolysis during mitochondrial distress. Furthermore, the effect of DFX on glycolysis was not limited to Mtb infection as DFX also boosted glycolytic metabolism in uninfected and LPS-stimulated cells. DFX also supports innate immune function by inducing IL1β production in human macrophages during early infection with Mtb and upon stimulation with LPS. Moreover, using hypoxia, Western blot and ChIP-qPCR analyses, we show that DFX modulates IL1β levels in these cells in a HIF1α-mediated manner. Collectively, our data suggests that DFX exhibits potential to enhance immunometabolic responses and augment host immune function during early Mtb infection, in selected clinical settings. |
| Databáze: | OpenAIRE |
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