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Research ArticleInflammation, Immunopharmacology, and Asthma

Annexin A1 Mediates Hydrogen Sulfide Properties in the Control of Inflammation

Vincenzo Brancaleone, Emma Mitidieri, Roderick J. Flower, Giuseppe Cirino and Mauro Perretti
Journal of Pharmacology and Experimental Therapeutics October 2014, 351 (1) 96-104; DOI: https://doi.org/10.1124/jpet.114.217034
Vincenzo Brancaleone
Department of Science, University of Basilicata, Potenza, Italy (V.B.); Department of Pharmacy, University of Naples, Naples, Italy (E.M., G.C.); and William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK (V.B., R.J.F., M.P.)
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Emma Mitidieri
Department of Science, University of Basilicata, Potenza, Italy (V.B.); Department of Pharmacy, University of Naples, Naples, Italy (E.M., G.C.); and William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK (V.B., R.J.F., M.P.)
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Roderick J. Flower
Department of Science, University of Basilicata, Potenza, Italy (V.B.); Department of Pharmacy, University of Naples, Naples, Italy (E.M., G.C.); and William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK (V.B., R.J.F., M.P.)
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Giuseppe Cirino
Department of Science, University of Basilicata, Potenza, Italy (V.B.); Department of Pharmacy, University of Naples, Naples, Italy (E.M., G.C.); and William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK (V.B., R.J.F., M.P.)
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Mauro Perretti
Department of Science, University of Basilicata, Potenza, Italy (V.B.); Department of Pharmacy, University of Naples, Naples, Italy (E.M., G.C.); and William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK (V.B., R.J.F., M.P.)
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Abstract

Hydrogen sulfide (H2S) is a gaseous mediator synthesized in mammalian tissues by three main enzymes—cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate-sulfurtransferase—and its levels increase under inflammatory conditions or sepsis. Since H2S and H2S-releasing molecules afford inhibitory properties in leukocyte trafficking, we tested whether endogenous annexin A1 (AnxA1), a glucocorticoid-regulated inhibitor of inflammation acting through formylated-peptide receptor 2 (ALX), could display intermediary functions in the anti-inflammatory profile of H2S. We first investigated whether endogenous AnxA1 could modulate H2S biosynthesis. To this end, a marked increase in CBS and/or CSE gene products was quantified by quantitative real-time polymerase chain reaction in aortas, kidneys, and spleens collected from AnxA1−/− mice, as compared with wild-type animals. When lipopolysaccharide-stimulated bone marrow–derived macrophages were studied, H2S-donor sodium hydrosulfide (NaHS) counteracted the increased expression of inducible nitric oxide synthase and cyclooxygenase 2 mRNA evoked by the endotoxin, yet it was inactive in macrophages harvested from AnxA1−/− mice. Next we studied the effect of in vivo administration of NaHS in a model of interleukin-1β (IL-1β)–induced mesenteric inflammation. AnxA1+/+ mice treated with NaHS (100 μmol/kg) displayed inhibition of IL-1β–induced leukocyte adhesion/emigration in the inflamed microcirculation, not observed in AnxA1−/− animals. These results were translated by testing human neutrophils, where NaHS (10–100 μM) prompted an intense mobilization (>50%) of AnxA1 from cytosol to cell surface, an event associated with inhibition of cell/endothelium interaction under flow. Taken together, these data strongly indicate the existence of a positive interlink between AnxA1 and H2S pathway, with nonredundant functions in the control of experimental inflammation.

Footnotes

    • Received June 5, 2014.
    • Accepted July 29, 2014.
  • This work was partly supported by the William Harvey Research Foundation (M.P.) and forms part of the research themes contributing to the translational research portfolio of Barts and The London National Institute for Health Research Cardiovascular Biomedical Research Unit. This work was also supported by the Wellcome Trust [Grant 086867/Z/08/Z].

  • This work has been previously presented as an oral presentation at the following conferences: Brancaleone V, Sampaio AL, Cirino G, Flower RJ, Perretti M (2011) A novel cross-talk in resolution: H2S activates the annexin A1 pathway. 10th World Congress of Inflammation; 2011 June 25–29; Paris, France. Vol 60 (Suppl 1), pp S291–S293, International Association of Inflammation Societies, London, UK; and Brancaleone V, Flower RJ, Cirino G, and Perretti M (2013) Annexin A1 mediates hydrogen sulfude effects in the control of inflammation. Second European Conference on the Biology of Hydrogen Sulfide; 2013 Sept 8–11; Exeter, UK. Vol 31 (Suppl 1), pp S21–S22, European Network on Gastrotransmitters, Patras, Greece.

  • dx.doi.org/10.1124/jpet.114.217034.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 1
1 Oct 2014
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Research ArticleInflammation, Immunopharmacology, and Asthma

Annexin A1 and Hydrogen Sulfide Cross-Talk in Inflammation

Vincenzo Brancaleone, Emma Mitidieri, Roderick J. Flower, Giuseppe Cirino and Mauro Perretti
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 96-104; DOI: https://doi.org/10.1124/jpet.114.217034

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Research ArticleInflammation, Immunopharmacology, and Asthma

Annexin A1 and Hydrogen Sulfide Cross-Talk in Inflammation

Vincenzo Brancaleone, Emma Mitidieri, Roderick J. Flower, Giuseppe Cirino and Mauro Perretti
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 96-104; DOI: https://doi.org/10.1124/jpet.114.217034
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