Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling
| Authors | |
|---|---|
| Year of publication | 2025 |
| Type | Article in Periodical |
| Magazine / Source | JOURNAL OF LIPID RESEARCH |
| MU Faculty or unit | |
| Citation | |
| web | https://www.sciencedirect.com/science/article/pii/S0022227524002104?via%3Dihub |
| Doi | http://dx.doi.org/10.1016/j.jlr.2024.100705 |
| Keywords | inflammation resolution; arachidonic acid; lipoxin; electrophile; formyl peptide receptor; lipoxygenase |
| 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 A(4) (LXA(4)), there are expanding concerns about the reported biological formation, detection, and signaling mechanisms ascribed to LXA(4) and related di- and tri-hydroxy omega-6 and omega-3 fatty acids. The generation and signaling actions of LXA(4) 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 LXA(4) synthesis, both LXA(4) and its 15-oxo-LXA(4) metabolite were undetectable in all conditions. Moreover, synthetic LXA(4) and the membrane-permeable 15-oxo-LXA(4) methyl ester, which rapidly de-esterified to 15-oxo-LXA(4), displayed no ligand activity for the putative LXA(4) receptor FPR2. Alternatively, 15-oxo-LXA(4), an electrophilic alpha,beta-unsaturated ketone, alkylates nucleophilic amino acids and can modulate redox-sensitive transcriptional regulatory protein and enzyme function. 15-oxo-LXA(4) activated nuclear factor (erythroid related factor 2)-like 2-regulated expression of anti-inflammatory and repair genes and inhibited NF kappa B-regulated pro-inflammatory mediator expression. Synthetic LXA(4) showed no impact on these macrophage anti-inflammatory and repair responses. In summary, these data show an absence of macrophage LXA(4) formation and receptor-mediated signaling actions of synthetic LXA(4).(Jlr) Rather, if present in sufficient concentrations, LXA(4) and other mono- and poly-hydroxylated unsaturated fatty acids synthesized by macrophages would be readily oxidized to electrophilic alpha,beta-unsaturated ketone products that modulate the redox-sensitive cysteine proteome via G-protein coupled receptor-independent mechanisms. |