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- Title
FPR2/ALX receptor expression and internalization are critical for lipoxin A<sub>4</sub> and annexin-derived peptide-stimulated phagocytosis.
- Authors
Maderna, Paola; Cottell, David C.; Toivonen, Tiina; Dufton, Neil; Dalli, Jesmond; Perretti, Mauro; Godson, Catherine
- Abstract
Lipoxins (LXs) are endogenously produced eicosanoids with well-described anti-inflammatory and proresolution activities, stimulating nonphlogistic phagocytosis of apoptotic cells by macrophages. LXA4 and the glucocorticoid-derived annexin Al peptide (Ac2-26) bind to a common G-protein-coupled receptor, termed FPR2/ALX. However, direct evidence of the involvement of FPR2/ALX in the anti-inflammatory and proresolution activity of LXA4 is still to be investigated. Here we describe FPR2/ALX trafficking in response to LXA4 and Ac2-26 stimulation. We have transfected cells with HA-tagged FPR2/ALX and studied receptor trafficking in unstimulated, LXA4 (1-10 nM)- and Ac2-26 (30 µM)-treated cells using multiple approaches that include immunofluorescent confocal microscopy, immuno-gold labeling of cryosections, and ELISA and investigated receptor trafficking in agonist-stimulated phagocytosis. We conclude that PKC-dependent internalization of FPR2/ALX is required for phagocytosis. Using bone marrow-derived macrophages (BMDMs) from mice in which the FPR2/ALX ortholog Fpr2 had been deleted, we observed the nonredundant function for this receptor in LXA4 and Ac2-26 stimulated phagocytosis of apoptotic neutrophils. LXA4 stimulated phagocytosis 1.7-fold above basal (P<0.001) by BMDMs from wild-type mice, whereas no effect was found on BMDMs from Fpr2-/- mice. Similarly, Ac2-26 stimulates phagocytosis by BMDMs from wild-type mice 1.5-fold above basal (P<0.05). However, Ac2-26 failed to stimulate phagocytosis by BMDMs isolated from Fpr2-/- mice relative to vehicle. These data reveal novel and complex mechanisms of the FPR2/ALX receptor trafficking and functionality in the resolution of inflammation.
- Subjects
G protein-coupled receptor kinases; LIPOXINS; ANNEXINS; PHAGOCYTOSIS; INFLAMMATION
- Publication
FASEB Journal, 2010, Vol 24, Issue 11, p4240
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.10-159913