Characterisation of the Fpr2 null mouse
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A novel Fpr2-/- mouse colony was used to explore the biology of Fpr2, a GPCR related to the human FPR2/ALX receptor that recognises lipoxin A4 (LXA4) annexin A1 (AnxA1) and serum amyloid A (SAA). Southern blotting, PCR and radio-ligand binding confirmed receptor deletion in the mouse Fpr2-/- colony. A GFP target/reporter strategy was employed in generating this novel transgenic to monitor promoter activity in living cells. This study revealed a propensity of Fpr2 for granulocytes, as well as a distinct role in macrophage (Mφ) maturation. Characterisation of Fpr2-/- Mφ revealed selective ERK phosphorylation triggered by the AnxA1-derived peptide Ac2-26, W peptide and Compound 43 (C43). Despite this Fpr-dependent signalling cascade via ERK, it was not a functional prognostic for cell migration in vitro or in vivo. Formyl peptide (fMLP) and serum amyloid A (SAA) chemotactic action was attenuated in Fpr2-/- Mφ, as well as the pro-phagocytic effects of Ac2-26 and LXA4. There was no observable naïve phenotype associated with Fpr2 depletion. To investigate the patho-physiology of Fpr2, acute and chronic inflammatory models were investigated in vivo to dissect different aspects of the receptor during disease progression. Notably Fpr2-/- mice exhibited stimulus specific discrepancies in inflammatory response. An acute IL-1β-induced air pouch model 6 revealed predominantly anti-migratory pharmacology of Fpr2 ligands, with a notable exception of SAA, discovered to be anti-migratory in the absence of Fpr2. Analysis of the full time-course of the zymosan peritonitis pointed to a subtle role for Fpr2 in neutrophil and monocyte migration as well as Mφ maturation. Of interest, exudate levels of SAA were augmented in Fpr2-/- mice revealing complex regulatory receptor/ligand circuits active during on-going inflammatory reactions. Finally, Fpr2-/- mice displayed pronounced arthritic responses upon treatment with the K/BxN arthrogenic serum, in comparison to their wild type controls. We conclude that Fpr2 can serve varied regulatory functions during the host response to inflammatory insult.
AuthorsDufton, Neil Peter
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