Nature Medicine8, 1296 - 1302 (2002)
Published online: 7 October 2002; | doi:10.1038/nm786
Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor
Mauro Perretti1, 5, Nan Chiang2, 5, Mylinh La1, Iolanda M. Fierro2, Stefano Marullo3, Stephen J Getting1, Egle Solito4
& Charles N. Serhan2
1
Department of Biochemical Pharmacology, William Harvey Research Institute, Bart's and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, UK
2
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
3
Department of Cell Biology, ICGM, Pavilion Gustave Roussy, Paris, France
4
Department of Neuroendocrinology, Faculty of Medicine, Imperial Collegee, London, UK
5
M.P. and N.C. contributed equally to this paper.
Aspirin (ASA) and dexamethasone (DEX) are widely used anti-inflammatory agents yet their mechanism(s) for blocking polymorphonuclear neutrophil (PMN) accumulation at sites of inflammation remains unclear. Here, we report that inhibition of PMN infiltration by ASA and DEX is a property shared by aspirin-triggered lipoxins (ATL) and the glucocorticoid-induced annexin 1 (ANXA1)-derived peptides that are both generated in vivo and act at the lipoxin A4 receptor (ALXR/FPRL1) to halt PMN diapedesis. These structurally diverse ligands specifically interact directly with recombinant human ALXR demonstrated by specific radioligand binding and function as well as immunoprecipitation of PMN receptors. In addition, the combination of both ATL and ANXA1-derived peptides limited PMN infiltration and reduced production of inflammatory mediators (that is, prostaglandins and chemokines) in vivo. Together, these results indicate functional redundancies in endogenous lipid and peptide anti-inflammatory circuits that are spatially and temporally separate, where both ATL and specific ANXA1-derived peptides act in concert at ALXR to downregulate PMN recruitment to inflammatory loci.
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