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Cited by 156Fatty Acid Research and HealthInflammatory mediators and NSAID effectsEicosanoids and Hypertension Pharmacology

Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome

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Werner, Markus, Jordan, Paul M., Romp, Erik, Czapka, Anna, Rao, Zhigang, Kretzer, Christian, Koeberle, Andreas, Garscha, Ulrike +5 more·2019·The FASEB Journal
DOI 10.1096/fj.201802509rPMC PMC6988863
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Abstract

Nonsteroidal anti‐inflammatory drugs interfere with the metabolism of arachidonic acid to proinflammatory prostaglandins and leukotrienes by targeting cyclooxygenases (COXs), 5‐lipoxygenase (LOX), or the 5‐LOX–activating protein (FLAP). These and related enzymes act in conjunction with marked crosstalk within a complex lipid mediator (LM) network where also specialized proresolving LMs (SPMs) are formed. Here, we present how prominent LM pathways can be differentially modulated in human proinflammatory M1 and proresolving M2 macrophage phenotypes that, upon exposure to Escherichia coli , produce either abundant prostaglandins and leukotrienes (M1) or SPMs (M2). Targeted liquid chromatography–tandem mass spectrometry–based metabololipidomics was applied to analyze and quantify the specific LM profiles. Besides expected on‐target actions, we found that: 1 ) COX or 15‐LOX‐1 inhibitors elevate inflammatory leukotriene levels, 2 ) FLAP and 5‐LOX inhibitors reduce leukotrienes in M1 but less so in M2 macrophages, 3 ) zileuton blocks resolution‐initiating SPM biosynthesis, whereas FLAP inhibition increases SPM levels, and 4 ) that the 15‐LOX‐1 inhibitor 3887 suppresses SPM formation in M2 macrophages. Conclusively, interference with discrete LM biosynthetic enzymes in different macrophage phenotypes considerably affects the LM metabolomes with potential consequences for inflammation‐resolution pharmacotherapy. Our data may allow better appraisal of the therapeutic potential of these drugs to intervene with inflammatory disorders.—Werner, M., Jordan, P. M., Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, A., Garscha, U., Pace, S., Claesson, H.‐E., Serhan, C. N., Werz, O., Gerstmeier, J. Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome. FASEB J. 33, 6140–6153 (2019). www.fasebj.org

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  • Many enzymes (e.g., COX and LOX) involved in generation of pro-inflammatory lipids are also important for biosynthesis of SPMs.

    “In addition, many enzymes (e.g., COX and LOX) involved in the generation of pro-inflammatory lipids are also important for the biosynthesis of SPMs.442”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [442]

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Authors
Werner, M., Jordan, P. M., Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, A., Garscha, U., Pace, S., Claesson, H., Serhan, C. N., Werz, O., & Gerstmeier, J.
Affiliations
  • Friedrich Schiller University Jena (DE)
  • Karolinska University Hospital (SE)
  • Brigham and Women's Hospital (US)
Corresponding author
  • Werz, Oliver
  • Gerstmeier, Jana
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2019-02-08
Volume
33
Issue
5
Pages
6140-6153
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.201802509r
PMC
PMC6988863
OpenAlex
W2914637605
Cited by
156
References
6
Citations by year
2026: 25 · 2025: 20 · 2024: 16 · 2023: 27 · 2022: 20 · 2021: 25 · 2020: 17 · 2019: 5
FWCI
13.32
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The FASEB Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (SFB1127, SFB1278)
  • National Institutes of Health
  • National Institute of General Medical Sciences (P01GM095467)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
Keywords
specialized pro-resolving mediators, lipid mediators, arachidonic acid metabolism, prostaglandins, leukotrienes, 15-lipoxygenase-1, 5-lipoxygenase, flaps, cyclooxygenase inhibitors, zileuton, M1 macrophages, M2 macrophages, Escherichia coli
MeSH terms
Adult, Anti-Inflammatory Agents, Non-Steroidal, Cells, Cultured, Humans, Lipoxygenase, Macrophages, Prostaglandin Antagonists, Prostaglandin-Endoperoxide Synthases, Prostaglandins, Leukotrienes, Lipoxygenase Inhibitors, Cyclooxygenase Inhibitors, Leukotriene Antagonists, Metabolome

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