Resolvin D1 Receptor Stereoselectivity and Regulation of Inflammation and Proresolving MicroRNAs
Open accessAbstract
Resolution of acute inflammation is an active process that involves the biosynthesis of specialized proresolving lipid mediators. Among them, resolvin D1 (RvD1) actions are mediated by two G protein-coupled receptors (GPCRs), ALX/FPR2 and GPR32, that also regulate specific microRNAs (miRNAs) and their target genes in novel resolution circuits. We report the ligand selectivity of RvD1 activation of ALX/FPR2 and GPR32. In addition to RvD1, its aspirin-triggered epimer and RvD1 analogs each dose dependently and effectively activated ALX/FPR2 and GPR32 in GPCR-overexpressing β-arrestin systems using luminescence and electric cell-substrate impedance sensing. To corroborate these findings in vivo, neutrophil infiltration in self-limited peritonitis was reduced in human ALX/FPR2-overexpressing transgenic mice that was further limited to 50% by RvD1 treatment with as little as 10 ng of RvD1 per mouse. Analysis of miRNA expression revealed that RvD1 administration significantly up-regulated miR-208a and miR-219 in exudates isolated from ALX/FPR2 transgenic mice compared with littermates. Overexpression of miR-208a in human macrophages up-regulated IL-10. In comparison, in ALX/FPR2 knockout mice, RvD1 neither significantly reduced leukocyte infiltration in zymosan-induced peritonitis nor regulated miR-208a and IL-10 in these mice. Together, these results demonstrate the selectivity of RvD1 interactions with receptors ALX/FPR2 and GPR32. Moreover, they establish a new molecular circuit that is operative in the resolution of acute inflammation activated by the proresolving mediator RvD1 involving specific GPCRs and miRNAs.
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SPMs and IL-10 promote efferocytosis.
“Both SPMs and IL-10 promote efferocytosis36,93,181–185”
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- Authors
- Krishnamoorthy, S., Recchiuti, A., Chiang, N., Fredman, G., & Serhan, C. N.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Serhan, Charles N.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 180
- Issue
- 5
- Pages
- 2018-2027
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC3349829
- OpenAlex
- W2119001835
- Cited by
- 283
- References
- 52
- Citations by year
- 2026: 17 · 2025: 11 · 2024: 11 · 2023: 17 · 2022: 18 · 2021: 31 · 2020: 22 · 2019: 27 · 2018: 23 · 2017: 23 · 2016: 18 · 2015: 20 · 2014: 21 · 2013: 18 · 2012: 6
- FWCI
- 19.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Brigham and Women's Hospital
- Queen Mary University of London
- National Institutes of Health (GM038765)
- National Institute of General Medical Sciences (R01GM038765)
- 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
- resolvin D1, FPR2/ALX, inflammation resolution, specialized pro-resolving mediators, microRNA regulation, miR-208a, miR-219, IL-10, neutrophil infiltration, peritonitis, macrophages, beta-arrestin
- MeSH terms
- beta-Arrestins, Acute Disease, Animals, Cells, Cultured, Docosahexaenoic Acids, Dose-Response Relationship, Drug, Gene Expression Regulation, Humans, Inflammation, Ligands, Macrophages, Mice, Transgenic, Peritonitis, Up-Regulation, Interleukin-10, Electric Impedance, Mice, Knockout, Arrestins, Neutrophil Infiltration, MicroRNAs, Receptors, G-Protein-Coupled, Receptors, Formyl Peptide, Receptors, Lipoxin, Mice
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