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Modulation of Phagocytosis of Apoptotic Neutrophils by Supernatant from Dexamethasone-Treated Macrophages and Annexin-Derived Peptide Ac_2–26¹

Paola Maderna^2,*, Simon Yona, Mauro Perretti and Catherine Godson^*

^* Department of Medicine and Therapeutics, The Conway Institute of Biomolecular and Biomedical Research and The Dublin Molecular Medicine Centre, University College Dublin, Dublin, Ireland; and Centre of Biochemical Pharmacology, William Harvey Research Institute, Queen Mary, University of London, Charterhouse Square, London, United Kingdom

Phagocytic clearance of apoptotic leukocytes plays an important role in the resolution of inflammation. The glucocorticoid-inducible protein annexin 1 and annexin 1-derived peptides show potent anti-inflammatory responses in acute and chronic inflammation. In this study, we report that the annexin 1-derived peptide (Ac_2–26) significantly stimulates nonphlogistic phagocytosis of apoptotic polymorphonuclear leukocytes (PMNs) by human monocyte-derived macrophages (M). Peptide Ac_2–26-stimulated phagocytosis is accompanied by rearrangement of the M actin cytoskeleton. To investigate the potential role of endogenous annexin on clearance of apoptotic cells, M were cultured for 5 days in the presence of dexamethasone. Supernatants collected from dexamethasone-treated M significantly enhanced the ability of naive M to engulf apoptotic PMNs. This effect was blocked by an annexin blocking Ab, by immunodepletion of the supernatants, and by the formyl peptide receptor/lipoxin receptor antagonist Boc1. In addition, we show that bone marrow-derived M from annexin 1-null mice present a 40% decreased phagocytosis of apoptotic PMNs compared with cells taken from littermate controls. In conclusion, these results emphasize the pivotal role of annexin 1 as mediator for clearance of apoptotic cells and expand its potential therapeutic role in controlling inflammatory diseases.

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