title: Toll-like receptor-4 agonist in post-haemorrhage pneumonia: role of dendritic and natural killer cells.
abstract: Haemorrhage-induced immunosuppression has been linked to nosocomial infections. We assessed the impact of monophosphoryl lipid A, a Toll/interleukin-1 receptor-domain-containing adaptor protein inducing interferon-biased Toll-like receptor-4 agonist currently used as a vaccine adjuvant in humans, on post-haemorrhage susceptibility to infection. We used a mouse model of post-haemorrhage pneumonia induced by methicillin-susceptible Staphylococcus aureus. Monophosphoryl lipid A was administered intravenously after haemorrhage and before pneumonia onset. Haemorrhage altered survival rate, increased lung damage (neutrophil accumulation, oedema and cytokine release) and altered the functions of dendritic and natural killer cells. Here, we show that monophosphoryl lipid A decreased systemic dissemination of S. aureus and dampened inflammatory lung lesions. Monophosphoryl lipid A partially restored the capacity for antigen presentation and the transcriptional activity in dendritic cells. Monophosphoryl lipid A did not restore the interferon-γ mRNA but prevented interleukin-10 mRNA overexpression in natural killer cells compared with untreated mice. Ex vivo monophosphoryl lipid A-stimulated dendritic cells or natural killer cells harvested from haemorrhaged animals were adoptively transferred into mice undergoing post-haemorrhage pneumonia. Stimulated dendritic cells (but not stimulated natural killer cells) improved the survival rate compared with mice left untreated. In vivo depletion of natural killer cells decreased survival rate of monophosphoryl lipid A-treated mice. Dendritic and natural killer cells are critically involved in the beneficial effects of monophosphoryl lipid A within post-haemorrhage pneumonia.
authors: Faculté de Médecine, Université de Nantes, Nantes.
authors: Antoine
authors: A
authors: Roquilly
authors: Alexis
authors: A
authors: Broquet
authors: Cedric
authors: C
authors: Jacqueline
authors: Laetitia
authors: L
authors: Gautreau
authors: Jean Pierre
authors: JP
authors: Segain
authors: Pierre
authors: P
authors: de Coppet
authors: Jocelyne
authors: J
authors: Caillon
authors: Frédéric
authors: F
authors: Altare
authors: Regis
authors: R
authors: Josien
authors: Karim
authors: K
authors: Asehnoune
mesh_terms: D000818:Animals; D018893:Bronchoalveolar Lavage; D003713:Dendritic Cells / Q000187:drug effects*; D042783:Endothelial Cells / Q000166:cytology; D006470:Hemorrhage / Q000150:complications*; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009195:Peroxidase / Q000378:metabolism; D010641:Phenotype; D011014:Pneumonia / Q000150:complications* / Q000628:therapy*; D013154:Spleen / Q000378:metabolism; D013211:Staphylococcus aureus / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists*
chemical_list: D008050:Lipid A; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D007371:Interferon-gamma; D009195:Peroxidase; C048436:monophosphoryl lipid A