|dc.description.abstract||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
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.||en_US