Carbon monoxide inhibits TLR-induced dendritic cell immunogenicity.
Heme oxygenase-1 (HO-1) exerts its functions via the catabolism of heme into carbon monoxide (CO), Fe(2+), and biliverdin, as well as by depletion of free heme. We have recently described that overexpression of HO-1 is associated with the tolerogenic capacity to dendritic cells (DCs) stimulated by LPS. In this study, we demonstrate that treatment of human monocyte-derived DCs with CO blocks TLR3 and 4-induced phenotypic maturation, secretion of proinflammatory cytokines, and alloreactive T cell proliferation, while preserving IL-10 production. Treatment of DCs with biliverdin, bilirubin, and deferoxamine or replenishing intracellular heme stores had no effect on DC maturation. HO-1 and CO inhibited LPS-induced activation of the IFN regulatory factor 3 pathway and their effects were independent of p38, ERK, and JNK MAPK. HO-1 and CO treatment also inhibited mouse DC maturation in vitro and mouse DC immunogenic properties in vivo, as shown by adoptive cell transfer in a transgenic model of induced diabetes. Thus, for the first time, our data show that CO treatment inhibits DC immunogenicity induced by TLR ligands and that blockade of IFN regulatory factor 3 is associated with this effect.
Rémy
Séverine
S
Institut National de Santé et de Recherche Médicale, Unité 643, Nantes, France.
Blancou
Philippe
P
Tesson
Laurent
L
Tardif
Virginie
V
Brion
Régis
R
Royer
Pierre Joseph
PJ
Motterlini
Roberto
R
Foresti
Roberta
R
Painchaut
Marion
M
Pogu
Sylvie
S
Gregoire
Marc
M
Bach
Jean Marie
JM
Anegon
Ignacio
I
Chauveau
Christine
C
D000818:Animals; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D051547:Heme Oxygenase-1 / Q000276:immunology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism
C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1