Details

Autor(en) / Beteiligte

• Dufton, Neil
• Hannon, Robert
• Brancaleone, Vincenzo
• Dalli, Jesmond
• Patel, Hetal B
• Gray, Mohini
• D'Acquisto, Fulvio
• Buckingham, Julia C
• Perretti, Mauro
• Flower, Roderick J

Titel

Anti-Inflammatory Role of the Murine Formyl-Peptide Receptor 2: Ligand-Specific Effects on Leukocyte Responses and Experimental Inflammation

Ist Teil von

• The Journal of immunology (1950), 2010-03, Vol.184 (5), p.2611-2619

Ort / Verlag

United States: Am Assoc Immnol

Erscheinungsjahr

2010

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.