Desferrioxamine Supports Metabolic Function in Primary Human Macrophages Infected With Mycobacterium tuberculosis

Frontiers in Immunology

Maureen J. O’Sullivan¹  Colin Kenny¹  Luke A. O’Neill²  Karl Michael Gogan³  Dónal J. Cox³  Simone Christa Tazoll³  James Joseph Phelan³  Sharee Ann Basdeo³  Cilian Ó Maoldomhnaigh³  Kate McQuaid³  Mary P. O’Sullivan³  Seónadh O’Leary³  Joseph Keane³ 

[1] National Children’s Research Centre, Our Lady’s Children’s Hospital, Dublin, Ireland;School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin, Ireland;TB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland;

关键词: glycolysis;    immunometabolism;    Warburg effect;    tuberculosis;    iron chelation;    iron metabolism;   

DOI  :  10.3389/fimmu.2020.00836

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown