@article {Brancaleone96, author = {Vincenzo Brancaleone and Emma Mitidieri and Roderick J. Flower and Giuseppe Cirino and Mauro Perretti}, title = {Annexin A1 Mediates Hydrogen Sulfide Properties in the Control of Inflammation}, volume = {351}, number = {1}, pages = {96--104}, year = {2014}, doi = {10.1124/jpet.114.217034}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Hydrogen sulfide (H2S) is a gaseous mediator synthesized in mammalian tissues by three main enzymes{\textemdash}cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate-sulfurtransferase{\textemdash}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{\textendash}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){\textendash}induced mesenteric inflammation. AnxA1+/+ mice treated with NaHS (100 μmol/kg) displayed inhibition of IL-1β{\textendash}induced leukocyte adhesion/emigration in the inflamed microcirculation, not observed in AnxA1-/- animals. These results were translated by testing human neutrophils, where NaHS (10{\textendash}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.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/351/1/96}, eprint = {https://jpet.aspetjournals.org/content/351/1/96.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }