Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling
The enzymatic oxidation of arachidonic acid is proposed to yield trihydroxytetraene species (termed lipoxins) that resolve inflammation via ligand activation of the formyl peptide receptor, FPR2. While cell and murine models activate signaling responses to synthetic lipoxins, primarily lipoxin A4 (L...
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Elsevier
2025-01-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524002104 |
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| author | Adolf Koudelka Gregory J. Buchan Veronika Cechova James P. O’Brien Emily R. Stevenson Crystal E. Uvalle Heng Liu Steven R. Woodcock Steven J. Mullett Cheng Zhang Bruce A. Freeman Stacy L. Gelhaus |
| author_facet | Adolf Koudelka Gregory J. Buchan Veronika Cechova James P. O’Brien Emily R. Stevenson Crystal E. Uvalle Heng Liu Steven R. Woodcock Steven J. Mullett Cheng Zhang Bruce A. Freeman Stacy L. Gelhaus |
| author_sort | Adolf Koudelka |
| collection | DOAJ |
| description | The enzymatic oxidation of arachidonic acid is proposed to yield trihydroxytetraene species (termed lipoxins) that resolve inflammation via ligand activation of the formyl peptide receptor, FPR2. While cell and murine models activate signaling responses to synthetic lipoxins, primarily lipoxin A4 (LXA4), there are expanding concerns about the reported biological formation, detection, and signaling mechanisms ascribed to LXA4 and related di- and tri-hydroxy ω-6 and ω-3 fatty acids. The generation and signaling actions of LXA4 and its primary 15-oxo metabolite were assessed in control, lipopolysaccharide-activated, and arachidonic acid-supplemented RAW264.7 and bone marrow-derived macrophages. Despite the expression of catalytically active enzymes required for LXA4 synthesis, both LXA4 and its 15-oxo-LXA4 metabolite were undetectable in all conditions. Moreover, synthetic LXA4 and the membrane-permeable 15-oxo-LXA4 methyl ester, which rapidly de-esterified to 15-oxo-LXA4, displayed no ligand activity for the putative LXA4 receptor FPR2. Alternatively, 15-oxo-LXA4, an electrophilic α,β-unsaturated ketone, alkylates nucleophilic amino acids and can modulate redox-sensitive transcriptional regulatory protein and enzyme function. 15-oxo-LXA4 activated nuclear factor (erythroid related factor 2)-like 2-regulated expression of anti-inflammatory and repair genes and inhibited NF-κB-regulated pro-inflammatory mediator expression. Synthetic LXA4 showed no impact on these macrophage anti-inflammatory and repair responses. In summary, these data show an absence of macrophage LXA4 formation and receptor-mediated signaling actions of synthetic LXA4. Rather, if present in sufficient concentrations, LXA4 and other mono- and poly-hydroxylated unsaturated fatty acids synthesized by macrophages would be readily oxidized to electrophilic α,β-unsaturated ketone products that modulate the redox-sensitive cysteine proteome via G-protein coupled receptor-independent mechanisms. |
| format | Article |
| id | doaj-art-f4e9a37bd9494f20b7d9b64027f93048 |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Journal of Lipid Research |
| spelling | doaj-art-f4e9a37bd9494f20b7d9b64027f930482025-01-30T05:12:37ZengElsevierJournal of Lipid Research0022-22752025-01-01661100705Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signalingAdolf Koudelka0Gregory J. Buchan1Veronika Cechova2James P. O’Brien3Emily R. Stevenson4Crystal E. Uvalle5Heng Liu6Steven R. Woodcock7Steven J. Mullett8Cheng Zhang9Bruce A. Freeman10Stacy L. Gelhaus11Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Pulmonary and Critical Care Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USAHealth Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USADepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USADepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; For correspondence: Stacy L. Gelhaus; Bruce A. FreemanDepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA; For correspondence: Stacy L. Gelhaus; Bruce A. FreemanThe enzymatic oxidation of arachidonic acid is proposed to yield trihydroxytetraene species (termed lipoxins) that resolve inflammation via ligand activation of the formyl peptide receptor, FPR2. While cell and murine models activate signaling responses to synthetic lipoxins, primarily lipoxin A4 (LXA4), there are expanding concerns about the reported biological formation, detection, and signaling mechanisms ascribed to LXA4 and related di- and tri-hydroxy ω-6 and ω-3 fatty acids. The generation and signaling actions of LXA4 and its primary 15-oxo metabolite were assessed in control, lipopolysaccharide-activated, and arachidonic acid-supplemented RAW264.7 and bone marrow-derived macrophages. Despite the expression of catalytically active enzymes required for LXA4 synthesis, both LXA4 and its 15-oxo-LXA4 metabolite were undetectable in all conditions. Moreover, synthetic LXA4 and the membrane-permeable 15-oxo-LXA4 methyl ester, which rapidly de-esterified to 15-oxo-LXA4, displayed no ligand activity for the putative LXA4 receptor FPR2. Alternatively, 15-oxo-LXA4, an electrophilic α,β-unsaturated ketone, alkylates nucleophilic amino acids and can modulate redox-sensitive transcriptional regulatory protein and enzyme function. 15-oxo-LXA4 activated nuclear factor (erythroid related factor 2)-like 2-regulated expression of anti-inflammatory and repair genes and inhibited NF-κB-regulated pro-inflammatory mediator expression. Synthetic LXA4 showed no impact on these macrophage anti-inflammatory and repair responses. In summary, these data show an absence of macrophage LXA4 formation and receptor-mediated signaling actions of synthetic LXA4. Rather, if present in sufficient concentrations, LXA4 and other mono- and poly-hydroxylated unsaturated fatty acids synthesized by macrophages would be readily oxidized to electrophilic α,β-unsaturated ketone products that modulate the redox-sensitive cysteine proteome via G-protein coupled receptor-independent mechanisms.http://www.sciencedirect.com/science/article/pii/S0022227524002104inflammation resolutionarachidonic acidlipoxinelectrophileformyl peptide receptorlipoxygenase |
| spellingShingle | Adolf Koudelka Gregory J. Buchan Veronika Cechova James P. O’Brien Emily R. Stevenson Crystal E. Uvalle Heng Liu Steven R. Woodcock Steven J. Mullett Cheng Zhang Bruce A. Freeman Stacy L. Gelhaus Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling Journal of Lipid Research inflammation resolution arachidonic acid lipoxin electrophile formyl peptide receptor lipoxygenase |
| title | Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling |
| title_full | Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling |
| title_fullStr | Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling |
| title_full_unstemmed | Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling |
| title_short | Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling |
| title_sort | lipoxin a4 yields an electrophilic 15 oxo metabolite that mediates fpr2 receptor independent anti inflammatory signaling |
| topic | inflammation resolution arachidonic acid lipoxin electrophile formyl peptide receptor lipoxygenase |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524002104 |
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