Lipoxin A4 yields an electrophilic 15-oxo metabolite that
mediates FPR2 receptor-independent anti-inflammatory signaling

J 2025

Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling

KOUDELKA, Adolf; Gregory J BUCHAN; Veronika ČECHOVÁ; James P O'BRIEN; Emily R STEVENSON et al.

Základní údaje

Originální název

Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling

Autoři

Vydání

JOURNAL OF LIPID RESEARCH, AMSTERDAM, ELSEVIER, 2025, 0022-2275

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Nizozemské království

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.100 v roce 2024

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14110/25:00140608

Organizační jednotka

Lékařská fakulta

Klíčová slova anglicky

inflammation resolution; arachidonic acid; lipoxin; electrophile; formyl peptide receptor; lipoxygenase

Štítky

14110513, 14110517, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 4. 2. 2025 14:25, Mgr. Tereza Miškechová

Anotace

V originále

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.

Citovat

KOUDELKA, Adolf; Gregory J BUCHAN; Veronika ČECHOVÁ; James P O'BRIEN; Emily R STEVENSON; Crystal E UVALLE; Heng LIU; Steven R WOODCOCK; Steven J MULLETT; Cheng ZHANG; Bruce A FREEMAN a Stacy L GELHAUS. Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling. JOURNAL OF LIPID RESEARCH. AMSTERDAM: ELSEVIER, 2025, roč. 66, č. 1, s. 1-16. ISSN 0022-2275. Dostupné z: https://doi.org/10.1016/j.jlr.2024.100705.

@article{2474642,
   author = {Koudelka, Adolf and Buchan, Gregory J and Čechová, Veronika and O'Brien, James P and Stevenson, Emily R and Uvalle, Crystal E and Liu, Heng and Woodcock, Steven R and Mullett, Steven J and Zhang, Cheng and Freeman, Bruce A and Gelhaus, Stacy L},
   article_location = {AMSTERDAM},
   article_number = {1},
   doi = {https://doi.org/10.1016/j.jlr.2024.100705},
   keywords = {inflammation resolution; arachidonic acid; lipoxin; electrophile; formyl peptide receptor; lipoxygenase},
   language = {eng},
   issn = {0022-2275},
   journal = {JOURNAL OF LIPID RESEARCH},
   title = {Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling},
   url = {https://www.sciencedirect.com/science/article/pii/S0022227524002104?via%3Dihub},
   volume = {66},
   year = {2025}
}

TY  - JOUR
ID  - 2474642
AU  - Koudelka, Adolf - Buchan, Gregory J - Čechová, Veronika - O'Brien, James P - Stevenson, Emily R - Uvalle, Crystal E - Liu, Heng - Woodcock, Steven R - Mullett, Steven J - Zhang, Cheng - Freeman, Bruce A - Gelhaus, Stacy L
PY  - 2025
TI  - Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling
JF  - JOURNAL OF LIPID RESEARCH
VL  - 66
IS  - 1
SP  - 1-16
EP  - 1-16
PB  - ELSEVIER
SN  - 00222275
KW  - inflammation resolution
KW  - arachidonic acid
KW  - lipoxin
KW  - electrophile
KW  - formyl peptide receptor
KW  - lipoxygenase
UR  - https://www.sciencedirect.com/science/article/pii/S0022227524002104?via%3Dihub
N2  - 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.
ER  -

KOUDELKA, Adolf; Gregory J BUCHAN; Veronika ČECHOVÁ; James P O'BRIEN; Emily R STEVENSON; Crystal E UVALLE; Heng LIU; Steven R WOODCOCK; Steven J MULLETT; Cheng ZHANG; Bruce A FREEMAN a Stacy L GELHAUS. Lipoxin A4 yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling. \textit{JOURNAL OF LIPID RESEARCH}. AMSTERDAM: ELSEVIER, 2025, roč.~66, č.~1, s.~1-16. ISSN~0022-2275. Dostupné z: https://doi.org/10.1016/j.jlr.2024.100705.

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