Efferocyte‐Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1‐Mediated Activation of Glycolysis
Abstract Clearance of multiple rounds of apoptotic cells (ACs) through continual efferocytosis is critical in the maintenance of organ function, the resolution of acute inflammation, and tissue repair. To date, little is known about the nature of mechanisms and factors that govern this fundamental p...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202304690 |
| _version_ | 1797305141012987904 |
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| author | Duco Steven Koenis Roberta de Matteis Vinothini Rajeeve Pedro Cutillas Jesmond Dalli |
| author_facet | Duco Steven Koenis Roberta de Matteis Vinothini Rajeeve Pedro Cutillas Jesmond Dalli |
| author_sort | Duco Steven Koenis |
| collection | DOAJ |
| description | Abstract Clearance of multiple rounds of apoptotic cells (ACs) through continual efferocytosis is critical in the maintenance of organ function, the resolution of acute inflammation, and tissue repair. To date, little is known about the nature of mechanisms and factors that govern this fundamental process. Herein, the authors reported that breakdown of ACs leads to upregulation of 12‐lipoxygenase in macrophages. This enzyme converts docosahexaenoic acid to maresin conjugates in tissue regeneration (MCTRs). The levels of these autacoids are elevated at sites of high apoptotic burden in vivo and in efferocytosing macrophages in vitro. Abrogation of MCTR production using genetic approaches limits the ability of macrophages to perform continual efferocytosis both in vivo and in vitro, an effect that is rescued by add‐back of MCTRs. Mechanistically, MCTR‐mediated priming of macrophages for continual efferocytosis is dependent on alterations in Rac1 signalling and glycolytic metabolism. Inhibition of Rac1 abolishes the ability of MCTRs to increase glucose uptake and efferocytosis in vitro, whereas inhibition of glycolysis limits the MCTR‐mediated increases in efferocytosis and tissue repair. Together, these findings demonstrate that upregulation of MCTRs by efferocytosing macrophages plays a central role in the regulation of continual efferocytosis via the autocrine and paracrine modulation of metabolic pathways. |
| first_indexed | 2024-03-08T00:20:37Z |
| format | Article |
| id | doaj.art-0eeb5d5bbff94f35b20157b4f0d0ff03 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-08T00:20:37Z |
| publishDate | 2024-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-0eeb5d5bbff94f35b20157b4f0d0ff032024-02-16T08:29:37ZengWileyAdvanced Science2198-38442024-02-01117n/an/a10.1002/advs.202304690Efferocyte‐Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1‐Mediated Activation of GlycolysisDuco Steven Koenis0Roberta de Matteis1Vinothini Rajeeve2Pedro Cutillas3Jesmond Dalli4Centre for Biochemical Pharmacology William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London London EC1M 6BQ UKCentre for Biochemical Pharmacology William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London London EC1M 6BQ UKCentre for Genomics and Computational Biology Barts Cancer Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London London EC1M 6BQ UKCentre for Genomics and Computational Biology Barts Cancer Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London London EC1M 6BQ UKCentre for Biochemical Pharmacology William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London London EC1M 6BQ UKAbstract Clearance of multiple rounds of apoptotic cells (ACs) through continual efferocytosis is critical in the maintenance of organ function, the resolution of acute inflammation, and tissue repair. To date, little is known about the nature of mechanisms and factors that govern this fundamental process. Herein, the authors reported that breakdown of ACs leads to upregulation of 12‐lipoxygenase in macrophages. This enzyme converts docosahexaenoic acid to maresin conjugates in tissue regeneration (MCTRs). The levels of these autacoids are elevated at sites of high apoptotic burden in vivo and in efferocytosing macrophages in vitro. Abrogation of MCTR production using genetic approaches limits the ability of macrophages to perform continual efferocytosis both in vivo and in vitro, an effect that is rescued by add‐back of MCTRs. Mechanistically, MCTR‐mediated priming of macrophages for continual efferocytosis is dependent on alterations in Rac1 signalling and glycolytic metabolism. Inhibition of Rac1 abolishes the ability of MCTRs to increase glucose uptake and efferocytosis in vitro, whereas inhibition of glycolysis limits the MCTR‐mediated increases in efferocytosis and tissue repair. Together, these findings demonstrate that upregulation of MCTRs by efferocytosing macrophages plays a central role in the regulation of continual efferocytosis via the autocrine and paracrine modulation of metabolic pathways.https://doi.org/10.1002/advs.202304690efferocytosismacrophagesmetabolismspecialized pro‐resolving mediators (SPM)tissue repair |
| spellingShingle | Duco Steven Koenis Roberta de Matteis Vinothini Rajeeve Pedro Cutillas Jesmond Dalli Efferocyte‐Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1‐Mediated Activation of Glycolysis Advanced Science efferocytosis macrophages metabolism specialized pro‐resolving mediators (SPM) tissue repair |
| title | Efferocyte‐Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1‐Mediated Activation of Glycolysis |
| title_full | Efferocyte‐Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1‐Mediated Activation of Glycolysis |
| title_fullStr | Efferocyte‐Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1‐Mediated Activation of Glycolysis |
| title_full_unstemmed | Efferocyte‐Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1‐Mediated Activation of Glycolysis |
| title_short | Efferocyte‐Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1‐Mediated Activation of Glycolysis |
| title_sort | efferocyte derived mctrs metabolically prime macrophages for continual efferocytosis via rac1 mediated activation of glycolysis |
| topic | efferocytosis macrophages metabolism specialized pro‐resolving mediators (SPM) tissue repair |
| url | https://doi.org/10.1002/advs.202304690 |
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