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Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production

Walter A. Baseler, Luke Davies Orcid Logo, Laura Quigley, Lisa A. Ridnour, Jonathan M. Weiss, S. Perwez Hussain, David A. Wink, Daniel W. McVicar

Redox Biology, Volume: 10, Pages: 12 - 23

Swansea University Author: Luke Davies Orcid Logo

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DOI (Published version): 10.1016/j.redox.2016.09.005

Abstract

Inflammatory maturation of M1 macrophages by proinflammatory stimuli such as toll like receptor ligands results in profound metabolic reprogramming resulting in commitment to aerobic glycolysis as evidenced by repression of mitochondrial oxidative phosphorylation (OXPHOS) and enhanced glucose utiliz...

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Published in: Redox Biology
ISSN: 2213-2317
Published: Elsevier BV 2016
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URI: https://cronfa.swan.ac.uk/Record/cronfa61704
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spelling 2022-11-07T11:12:05.4176835 v2 61704 2022-10-31 Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production ff080296775381560053d5e3a6e81745 0000-0001-7767-4060 Luke Davies Luke Davies true false 2022-10-31 MEDS Inflammatory maturation of M1 macrophages by proinflammatory stimuli such as toll like receptor ligands results in profound metabolic reprogramming resulting in commitment to aerobic glycolysis as evidenced by repression of mitochondrial oxidative phosphorylation (OXPHOS) and enhanced glucose utilization. In contrast, “alternatively activated” macrophages adopt a metabolic program dominated by fatty acid-fueled OXPHOS. Despite the known importance of these developmental stages on the qualitative aspects of an inflammatory response, relatively little is know regarding the regulation of these metabolic adjustments. Here we provide evidence that the immunosuppressive cytokine IL-10 defines a metabolic regulatory loop. Our data show for the first time that lipopolysaccharide (LPS)-induced glycolytic flux controls IL-10-production via regulation of mammalian target of rapamycin (mTOR) and that autocrine IL-10 in turn regulates macrophage nitric oxide (NO) production. Genetic and pharmacological manipulation of IL-10 and nitric oxide (NO) establish that metabolically regulated autocrine IL-10 controls glycolytic commitment by limiting NO-mediated suppression of OXPHOS. Together these data support a model where autocine IL-10 production is controlled by glycolytic flux in turn regulating glycolytic commitment by preserving OXPHOS via suppression of NO. We propose that this IL-10-driven metabolic rheostat maintains metabolic equilibrium during M1 macrophage differentiation and that perturbation of this regulatory loop, either directly by exogenous cellular sources of IL-10 or indirectly via limitations in glucose availability, skews the cellular metabolic program altering the balance between inflammatory and immunosuppressive phenotypes. Journal Article Redox Biology 10 12 23 Elsevier BV 2213-2317 1 12 2016 2016-12-01 10.1016/j.redox.2016.09.005 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 2022-11-07T11:12:05.4176835 2022-10-31T12:40:06.0031356 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Walter A. Baseler 1 Luke Davies 0000-0001-7767-4060 2 Laura Quigley 3 Lisa A. Ridnour 4 Jonathan M. Weiss 5 S. Perwez Hussain 6 David A. Wink 7 Daniel W. McVicar 8 61704__25665__46ce50ee257b4d978b89497f6fe80201.pdf 61704.pdf 2022-11-07T11:10:32.0007608 Output 2082369 application/pdf Version of Record true Copyright: 2016. This is an open access article under the CC BY-NC-ND license true eng http://creativecommons.org/licenses/by-nc-nd/4.0/
title Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production
spellingShingle Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production
Luke Davies
title_short Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production
title_full Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production
title_fullStr Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production
title_full_unstemmed Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production
title_sort Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production
author_id_str_mv ff080296775381560053d5e3a6e81745
author_id_fullname_str_mv ff080296775381560053d5e3a6e81745_***_Luke Davies
author Luke Davies
author2 Walter A. Baseler
Luke Davies
Laura Quigley
Lisa A. Ridnour
Jonathan M. Weiss
S. Perwez Hussain
David A. Wink
Daniel W. McVicar
format Journal article
container_title Redox Biology
container_volume 10
container_start_page 12
publishDate 2016
institution Swansea University
issn 2213-2317
doi_str_mv 10.1016/j.redox.2016.09.005
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
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description Inflammatory maturation of M1 macrophages by proinflammatory stimuli such as toll like receptor ligands results in profound metabolic reprogramming resulting in commitment to aerobic glycolysis as evidenced by repression of mitochondrial oxidative phosphorylation (OXPHOS) and enhanced glucose utilization. In contrast, “alternatively activated” macrophages adopt a metabolic program dominated by fatty acid-fueled OXPHOS. Despite the known importance of these developmental stages on the qualitative aspects of an inflammatory response, relatively little is know regarding the regulation of these metabolic adjustments. Here we provide evidence that the immunosuppressive cytokine IL-10 defines a metabolic regulatory loop. Our data show for the first time that lipopolysaccharide (LPS)-induced glycolytic flux controls IL-10-production via regulation of mammalian target of rapamycin (mTOR) and that autocrine IL-10 in turn regulates macrophage nitric oxide (NO) production. Genetic and pharmacological manipulation of IL-10 and nitric oxide (NO) establish that metabolically regulated autocrine IL-10 controls glycolytic commitment by limiting NO-mediated suppression of OXPHOS. Together these data support a model where autocine IL-10 production is controlled by glycolytic flux in turn regulating glycolytic commitment by preserving OXPHOS via suppression of NO. We propose that this IL-10-driven metabolic rheostat maintains metabolic equilibrium during M1 macrophage differentiation and that perturbation of this regulatory loop, either directly by exogenous cellular sources of IL-10 or indirectly via limitations in glucose availability, skews the cellular metabolic program altering the balance between inflammatory and immunosuppressive phenotypes.
published_date 2016-12-01T14:17:40Z
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