Faculté de Médecine, Université de Nantes, Nantes.
Eur Respir J. 2013 Nov;42(5):1365-78. doi: 10.1183/09031936.00152612. Epub 2013 Jan 11.
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.
出血引起的免疫抑制与医院获得性感染有关。我们评估了单磷酰脂质 A 的影响，单磷酰脂质 A 是一种 Toll/白细胞介素-1 受体结构域包含衔接蛋白诱导干扰素偏向 Toll 样受体-4 激动剂，目前在人类中用作疫苗佐剂。我们使用耐甲氧西林金黄色葡萄球菌诱导的出血后肺炎小鼠模型。在出血后和肺炎发作前静脉内给予单磷酰脂质 A。出血改变了存活率，增加了肺损伤（中性粒细胞聚集、水肿和细胞因子释放），并改变了树突状细胞和自然杀伤细胞的功能。在这里，我们表明单磷酰脂质 A 减少了金黄色葡萄球菌的全身扩散，并减轻了炎症性肺损伤。单磷酰脂质 A 部分恢复了树突状细胞的抗原呈递能力和转录活性。与未治疗的小鼠相比，单磷酰脂质 A 没有恢复干扰素-γ mRNA，但防止了自然杀伤细胞中白细胞介素-10 mRNA 的过度表达。从出血动物中收获的体外单磷酰脂质 A 刺激的树突状细胞或自然杀伤细胞被过继转移到经历出血后肺炎的小鼠中。与未治疗的小鼠相比，刺激的树突状细胞（而不是刺激的自然杀伤细胞）提高了存活率。体内耗尽自然杀伤细胞会降低单磷酰脂质 A 治疗小鼠的存活率。树突状细胞和自然杀伤细胞在出血后肺炎中单磷酰脂质 A 的有益作用中起关键作用。
