Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages
Pathological conditions associated with dysfunctional wound healing are characterized by impaired remodelling of extracellular matrix (ECM), increased macrophage infiltration, and chronic inflammation. Macrophages also play an important role in wound healing as they drive wound closure by secretion...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-02-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231722003639 |
| _version_ | 1828065316476813312 |
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| author | Sjors Maassen Britt Coenen Melina Ioannidis Karl Harber Pieter Grijpstra Jan Van den Bossche Geert van den Bogaart |
| author_facet | Sjors Maassen Britt Coenen Melina Ioannidis Karl Harber Pieter Grijpstra Jan Van den Bossche Geert van den Bogaart |
| author_sort | Sjors Maassen |
| collection | DOAJ |
| description | Pathological conditions associated with dysfunctional wound healing are characterized by impaired remodelling of extracellular matrix (ECM), increased macrophage infiltration, and chronic inflammation. Macrophages also play an important role in wound healing as they drive wound closure by secretion of molecules like transforming growth factor beta-1 (TGF-β). As the functions of macrophages are regulated by their metabolism, local administration of small molecules that alter this might be a novel approach for treatment of wound-healing disorders. Itaconate is a tricarboxylic acid (TCA) cycle-derived metabolite that has been associated with resolution of macrophage-mediated inflammation. However, its effects on macrophage wound healing functions are unknown. In this study, we investigated the effects of the membrane-permeable 4-octyl itaconate (4-OI) derivative on ECM scavenging by cultured human blood monocyte-derived macrophages (hMDM). We found that 4-OI reduced signalling of p38 mitogen-activated protein kinase (MAPK) induced by the canonical immune stimulus lipopolysaccharide (LPS). Likely as a consequence of this, the production of the inflammatory mediators like tumor necrosis factor (TNF)-α and cyclooxygenase (COX)-2 were also reduced. On the transcriptional level, 4-OI increased expression of the gene coding for TGF-β (TGFB1), whereas expression of the collagenase matrix metalloprotease-8 (MMP8) was reduced. Furthermore, surface levels of the anti-inflammatory marker CD36, but not CD206 and CD11c, were increased in these cells. To directly investigate the effect of 4-OI on scavenging of ECM by macrophages, we developed an assay to measure uptake of fibrous collagen. We observed that LPS promoted collagen uptake and that this was reversed by 4-OI-induced signaling of nuclear factor erythroid 2–related factor 2 (NRF2), a regulator of cellular resistance to oxidative stress and the reduced glycolytic capacity of the macrophage. These results indicate that 4-OI lowers macrophage inflammation, likely promoting a more wound-resolving phenotype. |
| first_indexed | 2024-04-10T23:13:02Z |
| format | Article |
| id | doaj.art-1e35df3e4aee4185a3465f881a886361 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-10T23:13:02Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-1e35df3e4aee4185a3465f881a8863612023-01-13T04:16:22ZengElsevierRedox Biology2213-23172023-02-0159102591Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophagesSjors Maassen0Britt Coenen1Melina Ioannidis2Karl Harber3Pieter Grijpstra4Jan Van den Bossche5Geert van den Bogaart6Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology, University of Groningen, Groningen, the NetherlandsDepartment of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology, University of Groningen, Groningen, the NetherlandsDepartment of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology, University of Groningen, Groningen, the NetherlandsDepartment of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Institute for Infection and Immunity, Cancer Centre Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the NetherlandsDepartment of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology, University of Groningen, Groningen, the NetherlandsDepartment of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Institute for Infection and Immunity, Cancer Centre Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the NetherlandsDepartment of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology, University of Groningen, Groningen, the Netherlands; Department of Medical Biology and Pathology, University Medical Center Groningen, Groningen, the Netherlands; Corresponding author. Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology, University of Groningen, Groningen, the Netherlands.Pathological conditions associated with dysfunctional wound healing are characterized by impaired remodelling of extracellular matrix (ECM), increased macrophage infiltration, and chronic inflammation. Macrophages also play an important role in wound healing as they drive wound closure by secretion of molecules like transforming growth factor beta-1 (TGF-β). As the functions of macrophages are regulated by their metabolism, local administration of small molecules that alter this might be a novel approach for treatment of wound-healing disorders. Itaconate is a tricarboxylic acid (TCA) cycle-derived metabolite that has been associated with resolution of macrophage-mediated inflammation. However, its effects on macrophage wound healing functions are unknown. In this study, we investigated the effects of the membrane-permeable 4-octyl itaconate (4-OI) derivative on ECM scavenging by cultured human blood monocyte-derived macrophages (hMDM). We found that 4-OI reduced signalling of p38 mitogen-activated protein kinase (MAPK) induced by the canonical immune stimulus lipopolysaccharide (LPS). Likely as a consequence of this, the production of the inflammatory mediators like tumor necrosis factor (TNF)-α and cyclooxygenase (COX)-2 were also reduced. On the transcriptional level, 4-OI increased expression of the gene coding for TGF-β (TGFB1), whereas expression of the collagenase matrix metalloprotease-8 (MMP8) was reduced. Furthermore, surface levels of the anti-inflammatory marker CD36, but not CD206 and CD11c, were increased in these cells. To directly investigate the effect of 4-OI on scavenging of ECM by macrophages, we developed an assay to measure uptake of fibrous collagen. We observed that LPS promoted collagen uptake and that this was reversed by 4-OI-induced signaling of nuclear factor erythroid 2–related factor 2 (NRF2), a regulator of cellular resistance to oxidative stress and the reduced glycolytic capacity of the macrophage. These results indicate that 4-OI lowers macrophage inflammation, likely promoting a more wound-resolving phenotype.http://www.sciencedirect.com/science/article/pii/S2213231722003639 |
| spellingShingle | Sjors Maassen Britt Coenen Melina Ioannidis Karl Harber Pieter Grijpstra Jan Van den Bossche Geert van den Bogaart Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages Redox Biology |
| title | Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages |
| title_full | Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages |
| title_fullStr | Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages |
| title_full_unstemmed | Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages |
| title_short | Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages |
| title_sort | itaconate promotes a wound resolving phenotype in pro inflammatory macrophages |
| url | http://www.sciencedirect.com/science/article/pii/S2213231722003639 |
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