The rheumatoid synovial environment alters fatty acid metabolism in human monocytes and enhances CCL20 secretion
© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissionsoup.com..
OBJECTIVES: Fatty acid oxidation (FAO) and glycolysis have been implicated in immune regulation and activation of macrophages. However, investigation of human monocyte intracellular metabolism in the context of the hypoxic and inflammatory rheumatoid arthritis (RA) synovium is lacking. We hypothesized that exposure of monocytes to the hypoxic and inflammatory RA environment would have a profound impact on their metabolic state, and potential to contribute to disease pathology.
METHODS: Human monocytes were isolated from buffy coats and exposed to hypoxia. Metabolic profiling of monocytes was carried out by LC-MS metabolomics. Inflammatory mediator release after LPS or RA-synovial fluid (RA-SF) stimulation was analysed by ELISA. FAO was inhibited by etomoxir or enhanced with exogenous carnitine supplementation. Transcriptomics of RA blood monocytes and RA-SF macrophages was carried out by microarray.
RESULTS: Hypoxia exacerbated monocyte-derived CCL20 and IL-1β release in response to LPS, and increased glycolytic intermediates at the expense of carnitines. Modulation of carnitine identified a novel role for FAO in the production of CCL20 in response to LPS. Transcriptional analysis of RA blood monocytes and RA-SF macrophages revealed that fatty acid metabolism was altered and CCL20 increased when monocytes enter the synovial environment. In vitro analysis of monocytes showed that RA-SF increases carnitine abundance and CCL20 production in hypoxia, which was exacerbated by exogenous carnitine.
CONCLUSION: This work has revealed a novel inflammatory mechanism in RA that links FAO to CCL20 production in human monocytes, which could subsequently contribute to RA disease pathogenesis by promoting the recruitment of Th17 cells and osteoclastogenesis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:59 |
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| Enthalten in: |
Rheumatology (Oxford, England) - 59(2020), 4 vom: 01. Apr., Seite 869-878 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rodgers, Lewis C [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.08.2020 Date Revised 21.08.2020 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/rheumatology/kez378 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM301067589 |
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| 100 | 1 | |a Rodgers, Lewis C |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The rheumatoid synovial environment alters fatty acid metabolism in human monocytes and enhances CCL20 secretion |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 21.08.2020 | ||
| 500 | |a Date Revised 21.08.2020 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissionsoup.com. | ||
| 520 | |a OBJECTIVES: Fatty acid oxidation (FAO) and glycolysis have been implicated in immune regulation and activation of macrophages. However, investigation of human monocyte intracellular metabolism in the context of the hypoxic and inflammatory rheumatoid arthritis (RA) synovium is lacking. We hypothesized that exposure of monocytes to the hypoxic and inflammatory RA environment would have a profound impact on their metabolic state, and potential to contribute to disease pathology | ||
| 520 | |a METHODS: Human monocytes were isolated from buffy coats and exposed to hypoxia. Metabolic profiling of monocytes was carried out by LC-MS metabolomics. Inflammatory mediator release after LPS or RA-synovial fluid (RA-SF) stimulation was analysed by ELISA. FAO was inhibited by etomoxir or enhanced with exogenous carnitine supplementation. Transcriptomics of RA blood monocytes and RA-SF macrophages was carried out by microarray | ||
| 520 | |a RESULTS: Hypoxia exacerbated monocyte-derived CCL20 and IL-1β release in response to LPS, and increased glycolytic intermediates at the expense of carnitines. Modulation of carnitine identified a novel role for FAO in the production of CCL20 in response to LPS. Transcriptional analysis of RA blood monocytes and RA-SF macrophages revealed that fatty acid metabolism was altered and CCL20 increased when monocytes enter the synovial environment. In vitro analysis of monocytes showed that RA-SF increases carnitine abundance and CCL20 production in hypoxia, which was exacerbated by exogenous carnitine | ||
| 520 | |a CONCLUSION: This work has revealed a novel inflammatory mechanism in RA that links FAO to CCL20 production in human monocytes, which could subsequently contribute to RA disease pathogenesis by promoting the recruitment of Th17 cells and osteoclastogenesis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CCL20 | |
| 650 | 4 | |a hypoxia | |
| 650 | 4 | |a inflammation | |
| 650 | 4 | |a metabolism | |
| 650 | 4 | |a monocytes | |
| 650 | 4 | |a rheumatoid arthritis | |
| 650 | 4 | |a synovial fluid | |
| 650 | 7 | |a CCL20 protein, human |2 NLM | |
| 650 | 7 | |a Chemokine CCL20 |2 NLM | |
| 650 | 7 | |a Enzyme Inhibitors |2 NLM | |
| 650 | 7 | |a Epoxy Compounds |2 NLM | |
| 650 | 7 | |a Fatty Acids |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a etomoxir |2 NLM | |
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| 650 | 7 | |a Carnitine |2 NLM | |
| 650 | 7 | |a S7UI8SM58A |2 NLM | |
| 700 | 1 | |a Cole, John |e verfasserin |4 aut | |
| 700 | 1 | |a Rattigan, Kevin M |e verfasserin |4 aut | |
| 700 | 1 | |a Barrett, Michael P |e verfasserin |4 aut | |
| 700 | 1 | |a Kurian, Nisha |e verfasserin |4 aut | |
| 700 | 1 | |a McInnes, Iain B |e verfasserin |4 aut | |
| 700 | 1 | |a Goodyear, Carl S |e verfasserin |4 aut | |
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