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Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor

Nature Medicine volume 8, pages 1296–1302 (2002)Cite this article

Abstract

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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Figure 1: Additive actions with DEX and ASA on PMN extravasation.
Figure 2: Direct interaction of ANXA1 with ALXR: competitive [125I-Tyr]Ac2-26 and [3H]LXA4 binding.
Figure 3: ANXA1 peptides directly interact with recombinant as well as endogenous PMN ALXR.
Figure 4: Both ATL and ANXA1 are generated in vivo and interact with ALXR.
Figure 5: Synergism with ANXA1-derived peptides and ATLa in vivo.

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Acknowledgements

We thank B. Schmidt for microscopic analyses, N. Petasis for synthetic LXA4 and ATL stable analogs (prepared for P01-DE13499), and M.H. Small for expert assistance in manuscript preparation. This work was supported in part by grants GM38765 and P01-DE13499 (to C.N.S.) and by grants P0567 and P0583 of the Arthritis Research Campaign UK (to M.P.).

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Author notes

  1. Mauro Perretti and Nan Chiang: M.P. and N.C. contributed equally to this paper.

Authors and Affiliations

  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

    Mauro Perretti, Mylinh La & Stephen J Getting

  2. Department of Anesthesiology, Center for Experimental Therapeutics and Reperfusion Injury, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Nan Chiang, Iolanda M. Fierro & Charles N. Serhan

  3. Department of Cell Biology, ICGM, Pavilion Gustave Roussy, Paris, France

    Stefano Marullo

  4. Department of Neuroendocrinology, Faculty of Medicine, Imperial Collegee, London, UK

    Egle Solito

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  1. Mauro Perretti
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Correspondence to Charles N. Serhan.

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Perretti, M., Chiang, N., La, M. et al. Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor. Nat Med 8, 1296–1302 (2002). https://doi.org/10.1038/nm786

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