Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis
In order to mount an appropriate immune response to infection, the macrophage must alter its metabolism by increasing aerobic glycolysis and concomitantly decreasing oxidative phosphorylation; a process known as the Warburg effect. Consequently, lactate, the end-product of glycolysis, accumulates in...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.663695/full |
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| author | Cilian Ó Maoldomhnaigh Donal J. Cox James J. Phelan Morgane Mitermite Dearbhla M. Murphy Gina Leisching Lorraine Thong Seónadh M. O’Leary Karl M. Gogan Kate McQuaid Amy M. Coleman Stephen V. Gordon Sharee A. Basdeo Joseph Keane |
| author_facet | Cilian Ó Maoldomhnaigh Donal J. Cox James J. Phelan Morgane Mitermite Dearbhla M. Murphy Gina Leisching Lorraine Thong Seónadh M. O’Leary Karl M. Gogan Kate McQuaid Amy M. Coleman Stephen V. Gordon Sharee A. Basdeo Joseph Keane |
| author_sort | Cilian Ó Maoldomhnaigh |
| collection | DOAJ |
| description | In order to mount an appropriate immune response to infection, the macrophage must alter its metabolism by increasing aerobic glycolysis and concomitantly decreasing oxidative phosphorylation; a process known as the Warburg effect. Consequently, lactate, the end-product of glycolysis, accumulates in the extracellular environment. The subsequent effect of lactate on surrounding macrophages is poorly understood. Mycobacterium tuberculosis (Mtb), the causative organism of Tuberculosis (TB), is phagocytosed by macrophages in the airways. Mtb infected macrophages upregulate aerobic glycolysis and effector functions to try to kill the bacteria. Our lab has previously shown that human macrophages produce lactate in response to infection with Mtb. Although lactate has largely been considered a waste product of aerobic glycolysis, we hypothesised that the presence of extracellular lactate would impact subsequent immunometabolic responses and modulate macrophage function. We demonstrate that the presence of exogenous lactate has an immediate effect on the cellular metabolism of resting human macrophages; causing a decrease in extracellular acidification rate (ECAR; analogous to the rate of glycolysis) and an increase in the oxygen consumption rate (OCR; analogous to oxidative phosphorylation). When lactate-treated macrophages were stimulated with Mtb or LPS, glycolysis proceeds to increase immediately upon stimulation but oxidative phosphorylation remains stable compared with untreated cells that display a decrease in OCR. This resulted in a significantly reduced ECAR/OCR ratio early in response to stimulation. Since altered metabolism is intrinsically linked to macrophage function, we examined the effect of lactate on macrophage cytokine production and ability to kill Mtb. Lactate significantly reduced the concentrations of TNF and IL-1β produced by human macrophages in response to Mtb but did not alter IL-10 and IL-6 production. In addition, lactate significantly improved bacillary clearance in human macrophages infected with Mtb, through a mechanism that is, at least in part, mediated by promoting autophagy. These data indicate that lactate, the product of glycolysis, has a negative feedback effect on macrophages resulting in an attenuated glycolytic shift upon subsequent stimulation and reduced pro-inflammatory cytokine production. Interestingly, this pro-resolution effect of lactate is associated with increased capacity to kill Mtb. |
| first_indexed | 2024-12-16T09:32:39Z |
| format | Article |
| id | doaj.art-a9b01451cc7f44639429c99ff0a2bc3b |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-16T09:32:39Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-a9b01451cc7f44639429c99ff0a2bc3b2022-12-21T22:36:30ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-10-011210.3389/fimmu.2021.663695663695Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosisCilian Ó Maoldomhnaigh0Donal J. Cox1James J. Phelan2Morgane Mitermite3Dearbhla M. Murphy4Gina Leisching5Lorraine Thong6Seónadh M. O’Leary7Karl M. Gogan8Kate McQuaid9Amy M. Coleman10Stephen V. Gordon11Sharee A. Basdeo12Joseph Keane13TB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, St James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin, IrelandTB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, St James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin, IrelandTB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, St James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin, IrelandSchool of Veterinary Medicine and Conway Institute, University College Dublin, Dublin, IrelandTB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, St James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin, IrelandTB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, St James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin, IrelandTB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, St James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin, IrelandTB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, St James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin, IrelandTB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, St James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin, IrelandTB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, St James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin, IrelandTB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, St James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin, IrelandSchool of Veterinary Medicine and Conway Institute, University College Dublin, Dublin, IrelandTB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, St James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin, IrelandTB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, St James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin, IrelandIn order to mount an appropriate immune response to infection, the macrophage must alter its metabolism by increasing aerobic glycolysis and concomitantly decreasing oxidative phosphorylation; a process known as the Warburg effect. Consequently, lactate, the end-product of glycolysis, accumulates in the extracellular environment. The subsequent effect of lactate on surrounding macrophages is poorly understood. Mycobacterium tuberculosis (Mtb), the causative organism of Tuberculosis (TB), is phagocytosed by macrophages in the airways. Mtb infected macrophages upregulate aerobic glycolysis and effector functions to try to kill the bacteria. Our lab has previously shown that human macrophages produce lactate in response to infection with Mtb. Although lactate has largely been considered a waste product of aerobic glycolysis, we hypothesised that the presence of extracellular lactate would impact subsequent immunometabolic responses and modulate macrophage function. We demonstrate that the presence of exogenous lactate has an immediate effect on the cellular metabolism of resting human macrophages; causing a decrease in extracellular acidification rate (ECAR; analogous to the rate of glycolysis) and an increase in the oxygen consumption rate (OCR; analogous to oxidative phosphorylation). When lactate-treated macrophages were stimulated with Mtb or LPS, glycolysis proceeds to increase immediately upon stimulation but oxidative phosphorylation remains stable compared with untreated cells that display a decrease in OCR. This resulted in a significantly reduced ECAR/OCR ratio early in response to stimulation. Since altered metabolism is intrinsically linked to macrophage function, we examined the effect of lactate on macrophage cytokine production and ability to kill Mtb. Lactate significantly reduced the concentrations of TNF and IL-1β produced by human macrophages in response to Mtb but did not alter IL-10 and IL-6 production. In addition, lactate significantly improved bacillary clearance in human macrophages infected with Mtb, through a mechanism that is, at least in part, mediated by promoting autophagy. These data indicate that lactate, the product of glycolysis, has a negative feedback effect on macrophages resulting in an attenuated glycolytic shift upon subsequent stimulation and reduced pro-inflammatory cytokine production. Interestingly, this pro-resolution effect of lactate is associated with increased capacity to kill Mtb.https://www.frontiersin.org/articles/10.3389/fimmu.2021.663695/fulllactatehumanmacrophageglycolysismetabolismtuberculosis |
| spellingShingle | Cilian Ó Maoldomhnaigh Donal J. Cox James J. Phelan Morgane Mitermite Dearbhla M. Murphy Gina Leisching Lorraine Thong Seónadh M. O’Leary Karl M. Gogan Kate McQuaid Amy M. Coleman Stephen V. Gordon Sharee A. Basdeo Joseph Keane Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis Frontiers in Immunology lactate human macrophage glycolysis metabolism tuberculosis |
| title | Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis |
| title_full | Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis |
| title_fullStr | Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis |
| title_full_unstemmed | Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis |
| title_short | Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis |
| title_sort | lactate alters metabolism in human macrophages and improves their ability to kill mycobacterium tuberculosis |
| topic | lactate human macrophage glycolysis metabolism tuberculosis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.663695/full |
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