Annexin A1 mediates hydrogen sulfide properties in the control of inflammation.

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.

• Authors: Vincenzo Brancaleone, Emma Mitidieri, Roderick J Flower, Giuseppe Cirino, Mauro Perretti
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 351 Issue 1 Pg. 96-104 (Oct 2014) ISSN: 1521-0103 [Electronic] United States
• PMID: 25077524 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Annexin A1
• Interleukin-1beta
• Lipopolysaccharides
• RNA, Messenger
• Sulfides
• annexin A1, mouse
• Nitric Oxide Synthase Type II
• Cyclooxygenase 2
• Cystathionine beta-Synthase
• Cystathionine gamma-Lyase
• sodium bisulfide
• Hydrogen Sulfide

Topics

• Animals
• Annexin A1 (genetics, metabolism)
• Aorta (metabolism)
• Bone Marrow Cells (drug effects, metabolism)
• Cell Adhesion
• Cell Movement
• Cyclooxygenase 2 (genetics, metabolism)
• Cystathionine beta-Synthase (genetics, metabolism)
• Cystathionine gamma-Lyase (genetics, metabolism)
• Female
• Humans
• Hydrogen Sulfide (metabolism)
• Inflammation (metabolism)
• Interleukin-1beta (pharmacology)
• Kidney (metabolism)
• Leukocytes (metabolism, physiology)
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Neutrophils (drug effects, metabolism)
• Nitric Oxide Synthase Type II (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Spleen (metabolism)
• Sulfides (pharmacology)