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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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References

  1. Cotran, R.S. Inflammation: Historical perspectives. in Inflammation: Basic Principles and Clinical Correlates 3rd edn. (eds. Gallin, J.I., Snyderman, R., Fearon, D.T., Haynes, B.F. & Nathan, C.) 5–10 (Lippincott Williams & Wilkins, Philadelphia, 1999).

    Google Scholar 

  2. Weissmann, G. Aspirin. Sci. Am. 264, 84–90 (1991).

    Article  CAS  Google Scholar 

  3. Patrono, C. Aspirin: new cardiovascular uses for an old drug. Am. J. Med. 110, 62S–65S (2001).

    Article  CAS  Google Scholar 

  4. Barnes, C.J., Hardman, W.E., Cameron, I.L. & Lee, M. Aspirin, but not sodium salicylate, indomethacin, or nabumetone, reversibly suppresses 1,2-dimethylhydrazine-induced colonic aberrant crypt foci in rats. Dig. Dis. Sci. 42, 920–926 (1997).

    Article  CAS  Google Scholar 

  5. Marcus, A.J. Aspirin as prophylaxis against colorectal cancer. N. Engl. J. Med. 333, 656–658 (1995).

    Article  CAS  Google Scholar 

  6. Samuelsson, B. From studies of biochemical mechanisms to novel biological mediators: Prostaglandin endoperoxides, thromboxanes and leukotrienes. in Les Prix Nobel: Nobel Prizes, Presentations, Biographies and Lectures 153–174 (Almqvist & Wiksell, Stockholm, 1982).

    Google Scholar 

  7. Vane, J.R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (London) New Biol. 231, 232–235 (1971).

    Article  CAS  Google Scholar 

  8. Hench, P.S., Kendall, E.C., Slocumb, C.H. & Polley, H.E. Proc. Staff Meet. Mayo Clin. 24, 181 (1949).

  9. Boumpas, D.T. & Wilder, R.L. Corticosteroids. in Arthritis and Allied Conditions: A Textbook of Rheumatology 14th edn. edn (ed. Koopman, W.J.) 827–847 (Lippincott Williams & Wilkins, Philadelphia, 2001).

    Google Scholar 

  10. Derry, S. & Loke, Y.K. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. Br. Med. J. 321, 1183–1187 (2000).

    Article  CAS  Google Scholar 

  11. Cronstein, B.N. & Weissmann, G. Targets for antiinflammatory drugs. Annu. Rev. Pharmacol. Toxicol. 35, 449–462 (1995).

    Article  CAS  Google Scholar 

  12. Sin, Y.M., Sedgwick, A.D., Chea, E.P. & Willoughby, D.A. Mast cells in newly formed lining tissue during acute inflammation: A six day air pouch model in the mouse. Ann. Rheum. Dis. 45, 873–877 (1986).

    Article  CAS  Google Scholar 

  13. Jick, H., Pinals, R.S., Ullian, R., Slone, D. & Muench, H. Dexamethasone and dexamethasone-aspirin in the treatment of chronic rheumatoid arthritis. Lancet 2, 1203–1205 (1965).

    Article  CAS  Google Scholar 

  14. Flower, R.J. & Rothwell, N.J. Lipocortin-1: Cellular mechanisms and clinical relevance. Trends Pharmacol. Sci. 15, 71–76 (1994).

    Article  CAS  Google Scholar 

  15. Lim, L.H., Solito, E., Russo-Marie, F., Flower, R.J. & Perretti, M. Promoting detachment of neutrophils adherent to murine postcapillary venules to control inflammation: effect of lipocortin 1. Proc. Natl. Acad. Sci USA 95, 14535–14539 (1998).

    Article  CAS  Google Scholar 

  16. Maridonneau-Parini, I., Errasfa, M. & Russo-Marie, F. Inhibition of O2-generation by dexamethasone is mimicked by lipocortin I in alveolar macrophages. J. Clin. Invest. 83, 1936–1940 (1989).

    Article  CAS  Google Scholar 

  17. Serhan, C.N., Takano, T., Chiang, N., Gronert, K. & Clish, C.B. Formation of endogenous “antiinflammatory” lipid mediators by transcellular biosynthesis: Lipoxins and aspirin-triggered lipoxins inhibit neutrophil recruitment and vascular permeability. Am. J. Respir. Crit. Care Med. 161, S95–S101 (2000).

    Article  CAS  Google Scholar 

  18. Chiang, N., Fierro, I.M., Gronert, K. & Serhan, C.N. Activation of lipoxin A4 receptors by aspirin-triggered lipoxins and select peptides evokes ligand-specific responses in inflammation. J. Exp. Med. 191, 1197–1207 (2000).

    Article  CAS  Google Scholar 

  19. Yokomizo, T., Izumi, T., Chang, K., Takuwa, T. & Shimizu, T. A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 387, 620–624 (1997).

    Article  CAS  Google Scholar 

  20. Gabay, C. & Kushner, I. Acute-phase proteins and other systemic responses to inflammation. N. Engl. J. Med. 340, 448–454 (1999).

    Article  CAS  Google Scholar 

  21. Su, S.B. et al. A seven-transmembrane, G protein-coupled receptor, FPRL1, mediates the chemotactic activity of serum amyloid A for human phagocytic cells. J. Exp. Med. 189, 395–402 (1999).

    Article  CAS  Google Scholar 

  22. Linke, R.P., Bock, V., Valet, G. & Rothe, G. Inhibition of the oxidative burst response of N-formyl peptide-stimulated neutrophils by serum amyloid-A protein. Biochem. Biophys. Res. Commun. 176, 1100–1105 (1991).

    Article  CAS  Google Scholar 

  23. Oliani, S.M., Paul-Clark, M.J., Christian, H.C., Flower, R.J. & Perretti, M. Neutrophil interaction with inflamed postcapillary venule endothelium alters annexin 1 expression. Am. J. Pathol. 158, 603–615 (2001).

    Article  CAS  Google Scholar 

  24. Perretti, M. et al. Mobilizing lipocortin 1 in adherent human leukocytes downregulates their transmigration. Nature Med. 2, 1259–1262 (1996).

    Article  CAS  Google Scholar 

  25. Walther, A., Riehemann, K. & Gerke, V. A novel ligand of the formyl peptide receptor: annexin I regulates neutrophil extravasation by interacting with the FPR. Mol. Cell. 5, 831–840 (2000).

    Article  CAS  Google Scholar 

  26. Perretti, M., Getting, S.J., Solito, E., Murphy, P.M. & Gao, J.L. Involvement of the receptor for formylated peptides in the in vivo anti-migratory actions of annexin 1 and its mimetics. Am. J. Pathol. 158, 1969–1973 (2001).

    Article  CAS  Google Scholar 

  27. Papayianni, A., Serhan, C.N. & Brady, H.R. Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells. J. Immunol. 156, 2264–2272 (1996).

    CAS  PubMed  Google Scholar 

  28. Kang, Y., Taddeo, B., Varai, G., Varga, J. & Fiore, S. Mutations of serine 236–237 and tyrosine 302 residues in the human lipoxin A4 receptor intracellular domains result in sustained signaling. Biochemistry 39, 13551–13557 (2000).

    Article  CAS  Google Scholar 

  29. Chiang, N. et al. Aspirin-triggered 15-epi-lipoxin A4 (ATL) generation by human leukocytes and murine peritonitis exudates: Development of a specific 15-epi-LXA4 ELISA. J. Pharmacol. Exp. Ther. 287, 779–790 (1998).

    CAS  PubMed  Google Scholar 

  30. Clish, C.B. et al. Local and systemic delivery of a stable aspirin-triggered lipoxin prevents neutrophil recruitment in vivo. Proc. Natl. Acad. Sci. USA 96, 8247–8252 (1999).

    Article  CAS  Google Scholar 

  31. Fadok, V.A. et al. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 28–29 (2000).

    Article  Google Scholar 

  32. Godson, C. et al. Cutting edge: Lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J. Immunol. 164, 1663–1667 (2000).

    Article  CAS  Google Scholar 

  33. Liu, Y. et al. Glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes. J. Immunol. 162, 3639–3646 (1999).

    CAS  PubMed  Google Scholar 

  34. Tsao, F.H.C., Meyer, K.C., Chen, X., Rosenthal, N.S. & Hu, J. Degradation of annexin I in bronchoalveolar lavage fluid from patients with cystic fibrosis. Am. J. Respir. Cell Mol. Biol. 18, 120–128 (1998).

    Article  CAS  Google Scholar 

  35. Ariel, A. et al. IL-2 induces T cell adherence to extracellular matrix: Inhibition of adherence and migration by IL-2 peptides generated by leukocyte elastase. J. Immunol. 161, 2465–2472 (1998).

    CAS  PubMed  Google Scholar 

  36. Yokomizo, T., Izumi, T. & Shimizu, T. Leukotriene B4: Metabolism and signal transduction. Arch. Biochem. Biophys. 385, 231–241 (2001).

    Article  CAS  Google Scholar 

  37. Perretti, M. et al. Acute inflammatory response in the mouse: Exacerbation by immunoneutralization of lipocortin 1. Br. J. Pharmacol. 117, 1145–1154 (1996).

    Article  CAS  Google Scholar 

  38. Cotter, M.J., Norman, K.E., Hellewell, P.G. & Ridger, V.C. A novel method for isolation of neutrophils from murine blood using negative immunomagnetic separation. Am. J. Pathol. 159, 473–481 (2001).

    Article  CAS  Google Scholar 

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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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