Anti-inflammatory role of the murine formyl-peptide receptor 2: ligand-specific effects on leukocyte responses and experimental inflammation.
The human formyl-peptide receptor (FPR)-2 is a G protein-coupled receptor that transduces signals from lipoxin A(4), annexin A1, and serum amyloid A (SAA) to regulate inflammation. In this study, we report the creation of a novel mouse colony in which the murine FprL1 FPR2 homologue, Fpr2, has been deleted and describe its use to explore the biology of this receptor. Deletion of murine fpr2 was verified by Southern blot analysis and PCR, and the functional absence of the G protein-coupled receptor was confirmed by radioligand binding assays. In vitro, Fpr2(-/-) macrophages had a diminished response to formyl-Met-Leu-Phe itself and did not respond to SAA-induced chemotaxis. ERK phosphorylation triggered by SAA was unchanged, but that induced by the annexin A1-derived peptide Ac2-26 or other Fpr2 ligands, such as W-peptide and compound 43, was attenuated markedly. In vivo, the antimigratory properties of compound 43, lipoxin A(4), annexin A1, and dexamethasone were reduced notably in Fpr2(-/-) mice compared with those in wild-type littermates. In contrast, SAA stimulated neutrophil recruitment, but the promigratory effect was lost following Fpr2 deletion. Inflammation was more marked in Fpr2(-/-) mice, with a pronounced increase in cell adherence and emigration in the mesenteric microcirculation after an ischemia-reperfusion insult and an augmented acute response to carrageenan-induced paw edema, compared with that in wild-type controls. Finally, Fpr2(-/-) mice exhibited higher sensitivity to arthrogenic serum and were completely unable to resolve this chronic pathology. We conclude that Fpr2 is an anti-inflammatory receptor that serves varied regulatory functions during the host defense response. These data support the development of Fpr2 agonists as novel anti-inflammatory therapeutics.
Dufton
Neil
N
The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London.
Hannon
Robert
R
The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London.
Brancaleone
Vincenzo
V
The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London.
Dalli
Jesmond
J
The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London.
Patel
Hetal B
HB
The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London.
Gray
Mohini
M
Medical Research Council Centre for Inflammation, Edinburgh, United Kingdom.
D'Acquisto
Fulvio
F
The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London.
Buckingham
Julia C
JC
Office of Pro-Rector (Education), Imperial College London, London.
Perretti
Mauro
M
The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London.
Flower
Roderick J
RJ
The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London.
D000595:Amino Acid Sequence; D000818:Animals; D017305:Annexin A1 / Q000378:metabolism / Q000494:pharmacology; D002351:Carrageenan; D002633:Chemotaxis / Q000187:drug effects; D004487:Edema / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015151:Immunoblotting; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D008024:Ligands; D044045:Lipoxins / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015054:Zymosan
D017305:Annexin A1; D008024:Ligands; D044045:Lipoxins; D010455:Peptides; D044042:Receptors, Formyl Peptide; C096153:annexin A1 peptide (2-26); C481578:formyl peptide receptor 2, mouse; C040527:lipoxin A4; D009240:N-Formylmethionine Leucyl-Phenylalanine; C042205:methionyl-leucyl-phenylalanine; D002351:Carrageenan; D015054:Zymosan; D048049:Extracellular Signal-Regulated MAP Kinases