ABSTRACT
Title
A novel cross talk in resolution: H2S activates the Annexin A1 pathway
Authors
V. Brancaleone1,2, A.L.F. Sampaio2, R. Flower2, G. Cirino1 & M. Perretti2
1- Dept Exp Pharmacology, University of Naples FEDERICO, II, Italy
2- WHRI, Barts and the London SMD, QMUL, London, UK
1- Dept Exp Pharmacology, University of Naples FEDERICO, II, Italy
2- WHRI, Barts and the London SMD, QMUL, London, UK
Abstract
Hydrogen sulphide (H2S), a gaseous mediator synthesized in several mammalian tissues by two main enzymes CBS and CSE, increases under inflammatory conditions or sepsis [Li et al., 2009; Zhang et al., 2007]. Since H2S and H2S-releasing molecules afford potent inhibitory properties on the process of leukocyte trafficking [Andruski et al., 2008; Wallace et al., 2009], we tested whether endogenous Annexin A1 (AnxA1) could display intermediary functions.
Treatment of human PMNs the H2S donor NaHS (10-100µM) provoked prompted and intense mobilization (>50%) of AnxA1 from the cytosolic pool to the cell surface, supporting the inhibitory effects of the gas in the flow chamber assay. Such in vitro actions could be translated in analyses of the inflamed microcirculation, where NaHS (100 µmol/kg s.c., -30min) afforded marked inhibition of IL-1-induced cell adhesion and emigration in the mesenteric vessels of wild type, but not AnxA1-/-, mice.
Next, we investigated whether endogenous AnxA1 could modulate H2S synthesis, indicating existence of a positive circuit. To this end, a marked increase in CBS and/or CSE expression in a variety of tissues (aorta, kidney, spleen)tested from AnxA1-/- mice, as compared to wild type animals, was quantified by qPCR. Moreover, NaHS was able to counteract the increase in expression in iNOS and COX2 (4-fold and 7-fold reduction, respectively) upon LPS-stimulation of bone marrow derived macrophages (BMDM), though it was totally inactive in cells prepared from AnxA1-/- mice.
Taken together, these data strongly suggest – for the first time – the existence of a positive interlink between AnxA1 and the H2S pathway, providing a novel mechanistic explanation for the exquisite properties of H2S in the control of experimental inflammation. These finding may be relevant to innovative discovery programmes aiming at harnessing the biological properties of H2S.
Li et al., J Cell Mol Med. 2009, 13:2684-92
Zhang et al., J Leukoc Biol. 2007, 82:894-905
Andruski et al., Am J Physiol Regul Integr Comp Physiol. 2008, 295:R814-20
Wallace et al., Gastroenterology. 2009, 137:569-78
Treatment of human PMNs the H2S donor NaHS (10-100µM) provoked prompted and intense mobilization (>50%) of AnxA1 from the cytosolic pool to the cell surface, supporting the inhibitory effects of the gas in the flow chamber assay. Such in vitro actions could be translated in analyses of the inflamed microcirculation, where NaHS (100 µmol/kg s.c., -30min) afforded marked inhibition of IL-1-induced cell adhesion and emigration in the mesenteric vessels of wild type, but not AnxA1-/-, mice.
Next, we investigated whether endogenous AnxA1 could modulate H2S synthesis, indicating existence of a positive circuit. To this end, a marked increase in CBS and/or CSE expression in a variety of tissues (aorta, kidney, spleen)tested from AnxA1-/- mice, as compared to wild type animals, was quantified by qPCR. Moreover, NaHS was able to counteract the increase in expression in iNOS and COX2 (4-fold and 7-fold reduction, respectively) upon LPS-stimulation of bone marrow derived macrophages (BMDM), though it was totally inactive in cells prepared from AnxA1-/- mice.
Taken together, these data strongly suggest – for the first time – the existence of a positive interlink between AnxA1 and the H2S pathway, providing a novel mechanistic explanation for the exquisite properties of H2S in the control of experimental inflammation. These finding may be relevant to innovative discovery programmes aiming at harnessing the biological properties of H2S.
Li et al., J Cell Mol Med. 2009, 13:2684-92
Zhang et al., J Leukoc Biol. 2007, 82:894-905
Andruski et al., Am J Physiol Regul Integr Comp Physiol. 2008, 295:R814-20
Wallace et al., Gastroenterology. 2009, 137:569-78