Dendritic Cells Modulate Lung Response to Pseudomonas aeruginosa in a Murine Model of Sepsis-Induced Immune Dysfunction
Dendritic Cells Modulate Lung Response to Pseudomonas aeruginosa in a Murine Model of Sepsis-Induced Immune Dysfunction
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DOI：
10.4049/jimmunol.181.12.8513
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发表时间：
2008-12-15
影响因子：
4.4
通讯作者：
Chiche, Jean-Daniel
中科院分区：
文献类型：
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作者：
Pene, Frederic;Zuber, Benjamin;Chiche, Jean-Daniel
病原体引起的宿主感染触发先天免疫应答，导致全身炎症应答，通常随后是免疫功能障碍，这可能有利于继发性感染的出现。树突状细胞（Dendritic cells，DCs）是连接先天免疫和获得性免疫的纽带，可能是脓毒症免疫功能紊乱的重要调节细胞。我们在亚致死性多微生物败血症（盲肠结扎和穿刺，CLP）的海洋模型中评估了DC对肺防御的贡献。在该模型中，骨髓来源的DC（BMDCs）保留了不成熟的表型，与IL-12 p70释放能力降低和T细胞淋巴细胞引发受损相关。CLP手术后8天，我们通过气管内滴注5 × 106 CFU的铜绿假单胞菌诱导继发性肺部感染。尽管所有假手术小鼠均存活，但80%的CLP后小鼠在继发性肺炎后死亡。CLP后小鼠表现出明显的肺损伤，早期募集中性粒细胞，细胞因子失衡，IL-12 p70的产生减少，IL-10的释放增加，但没有缺陷的细菌肺清除，而全身细菌传播几乎是恒定的。将外源性BMDC同时肺内给药至用铜绿假单胞菌攻击的CLP后小鼠中显著改善了存活率。BMDCs没有改善细菌肺清除，但延迟中性粒细胞募集，强烈减弱TNF-α的早期峰值，并恢复了适当的IL-12 p70/IL-10平衡后CLP小鼠。因此，在继发性铜绿假单胞菌肺炎的相关模型中，BMDC的过继转移逆转了脓毒症诱导的免疫功能障碍。出乎意料的是，BMDC的作用机制并不涉及增强的抗菌活性，而是通过抑制肺部炎症反应而发生的。免疫学杂志，2008，181：851-3-8520.
Host infection by pathogens triggers an innate immune response leading to a systemic inflammatory response, often followed by an immune dysfunction which can favor the emergence of secondary infections. Dendritic cells (DCs) link innate and adaptive immunity and may he centrally involved in the regulation of sepsis-induced immune dysfunction. We assessed the contribution of DCs to lung defense in a marine model of sublethal polymicrobial sepsis (cecal ligature and puncture, CLP). In this model, bone marrow-derived DCs (BMDCs) retained an immature phenotype, associated with decreased capacity of IL-12p70 release and impaired priming of T cell lymphocytes. Eight days after CLP surgery, we induced a secondary pulmonary infection through intratracheal instillation of 5 x 10(6) CFUs of Pseudomonas aeruginosa. Whereas all sham-operated mice survived, 80% of post-CLP mice died after secondary pneumonia. Post-CLP mice exhibited marked lung damage with early recruitment of neutrophils, cytokine imbalance with decreased IL-12p70 production, and increased IL-10 release, but no defective bacterial lung clearance, while systemic bacterial dissemination was almost constant. Concomitant intrapulmonary administration of exogenous BMDCs into post-CLP mice challenged with P. aeruginosa dramatically improved survival. BMDCs did not improve bacterial lung clearance, but delayed neutrophil recruitment, strongly attenuated the early peak of TNF-alpha and restored an adequate IL-12p70/IL-10 balance in post-CLP mice. Thus, adoptive transfer of BMDCs reversed sepsis-induced immune dysfunction in a relevant model of secondary P. aeruginosa pneumonia. Unexpectedly, the mechanism of action of BMDCs did not involve enhanced antibacterial activity, but occurred by dampening the pulmonary inflammatory response. The Journal of Immunology, 2008, 181:851-3-8520.