title: Carbon monoxide down-modulates Toll-like receptor 4/MD2 expression on innate immune cells and reduces endotoxic shock susceptibility.
abstract: Carbon monoxide (CO) has been recently reported as the main anti-inflammatory mediator of the haem-degrading enzyme haem-oxygenase 1 (HO-1). It has been shown that either HO-1 induction or CO treatment reduces the ability of monocytes to respond to inflammatory stimuli, such as lipopolysaccharide (LPS), due to an inhibition of the signalling pathways leading to nuclear factor-κB, mitogen-activated protein kinases and interferon regulatory factor 3 activation. Hence, it has been suggested that CO impairs the stimulation of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD2) complex located on the surface of immune cells. However, whether CO can negatively modulate the surface expression of the TLR4/MD2 complex in immune cells remains unknown. Here we report that either HO-1 induction or treatment with CO decreases the surface expression of TLR4/MD2 in dendritic cells (DC) and neutrophils. In addition, in a septic shock model of mice intraperitoneally injected with lipopolysaccharide (LPS), prophylactic treatment with CO protected animals from hypothermia, weight loss, mobility loss and death. Further, mice pre-treated with CO and challenged with LPS showed reduced recruitment of DC and neutrophils to peripheral blood, suggesting that this gas causes a systemic tolerance to endotoxin challenge. No differences in the amount of innate cells in lymphoid tissues were observed in CO-treated mice. Our results suggest that CO treatment reduces the expression of the TLR4/MD2 complex on the surface of myeloid cells, which renders them resistant to LPS priming in vitro, as well as in vivo in a model of endotoxic shock.
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; INSERM, UMR 1064, Nantes, France.
authors.forename: Sebastián A
authors.initials: SA
authors.lastname: Riquelme
authors.forename: Susan M
authors.initials: SM
authors.lastname: Bueno
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Kalergis
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D002248:Carbon Monoxide / Q000494:pharmacology*; D002465:Cell Movement / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D007035:Hypothermia / Q000188:drug therapy / Q000517:prevention & control; D007249:Inflammation / Q000276:immunology; D018836:Inflammation Mediators / Q000494:pharmacology; D050838:Interferon Regulatory Factor-3 / Q000276:immunology; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96 / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D012772:Shock, Septic / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D000963:Antimetabolites; D018836:Inflammation Mediators; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1
keywords: Toll-like receptor 4; carbon monoxide; haem-oxygenase 1; lipopolysaccharide; septic shock