Dysregulation of Innate Immune response in Bacterial Pneumonia by Cardiolipin

心磷脂对细菌性肺炎先天免疫反应的失调

• 批准号: 8643331
• 负责人: Prabir Ray
• 金额: $ 40.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-03 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8643331
• 关键词: Acute Lung Injury; Address; Affect; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Bacteria; Bacterial Infections; Bacterial Pneumonia; Biological Assay; Cardiolipins; Cell Death; Cell Line; Cell Survival; Cells; Data; Distress; Dominant-Negative Mutation; Epithelial Cells; Generations; Goals; Gram-Negative Bacteria; Homeostasis; ITGAM gene; Image; Immune response; Immune system; Immunity; Immunosuppressive Agents; Infection; Inflammation; Inflammatory Response; Injury; Interleukin-10; Invaded; Kinetics; Klebsiella pneumonia bacterium; Lead; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Modeling; Monitor; Mus; Myelogenous; Myeloid Cells; Neutrophil Infiltration; Nosocomial pneumonia; Organ; Patients; Phagolysosome; Phase; Phenotype; Phosphatidic Acid; Phospholipase; Play; Pneumonia; Population; Production; Recruitment Activity; Reporting; Resolution; Role; Signal Transduction; Silicon Dioxide; Source; Structure of parenchyma of lung; Structure-Activity Relationship; Suppressor-Effector T-Lymphocytes; System; TLR7 gene; Testing; Therapeutic Intervention; Time; Tissues; Wild Type Mouse; base; cell type; cytokine; in vivo; lung injury; macrophage; microbial; mutant; neutrophil; novel; pathogen; prevent; programs; response

The innate immune system of the host plays an essential role in clearance of pathogens from the lung and other organs in which both neutrophils and macrophages play important roles. However, subsequent to pathogen clearance, the neutrophil influx needs to be curbed and dead neutrophils removed to minimize tissue damage. This response is sometimes compromised in pneumonia in which persistent neutrophilic inflammation causes collateral damage to lung tissue causing acute lung injury. IL-10 is an important immunosuppressive cytokine whose neutralization or absence has been shown to affect resolution of inflammation evidenced by persistent immunopathologic injury observed after infection by diverse pathogens. However, IL-10 is not uniformly beneficial during pathogen infection. At early time points after infection with the Gram negative bacterium Klebsiella pneumoniae that causes nosocomial pneumonia, presence of IL-10 was found to impede bacterial clearance. We present our novel observation that absence of IL-10 later after infection causes persistent inflammation in the lung. We have recently reported on the identification of a lung cell type resembling myeloid-derived suppressor cells (MDSCs) that expands in response to LPS and exerts immunosuppressive functions via IL-10 production. We show that this cell type is the major source of IL-10 in the total lung. So, if IL-10 provided by this cell type helps to resolve inflammation and restore homeostasis after pathogen infection, why does the program sometimes fail in pneumonia? We have identified a novel mechanism by which cardiolipin (CL), whose levels significantly increase in the lungs of pneumonia patients, compromises host immunity by suppressing production of the anti-inflammatory cytokine IL-10. CL interacts with TLR7 and generates the potent PPARy antagonist cyclic phosphatidic acid (cPA) in MDSC-Iike cells. Our findings lead us to hypothesize that 1) CL is recruited to phagolysosomes due to interaction between CL and TLR7 where phospholipase 02 is involved in the generation of cPA from CL. 2) Antagonism of PPARy activity by cPA inhibits IL-10 production compromising an anti-inflammatory mechanism in the resolution of bacterial pneumonia. To address these hypotheses we will: Aim 1. Study the role of CL-TLR7 interaction in suppression of IL-10 production by CL and in regulating bacterial pneumonia. Aim 2. Investigate whether disabling PLD2 or boosting PPARy preserves late phase IL-10 production from lung myeloid cells in the presence of CL.

宿主的先天免疫系统在从肺和其他器官清除病原体中起着重要作用，其中嗜中性粒细胞和巨噬细胞都起着重要作用。然而，在病原体清除之后，需要抑制中性粒细胞流入并去除死亡的中性粒细胞以使组织损伤最小化。这种反应有时在肺炎中受到损害，其中持续的嗜酸性炎症引起肺组织的附带损伤，引起急性肺损伤。IL-10是一种重要的免疫抑制细胞因子，其中和或不存在已显示影响炎症的消退，这通过在被多种病原体感染后观察到的持续免疫病理损伤来证明。然而，IL-10在病原体感染期间并不是均匀有益的。在感染引起医院获得性肺炎的革兰氏阴性细菌肺炎克雷伯氏菌后的早期时间点，发现IL-10的存在阻碍细菌清除。我们提出了我们的新观察，即感染后IL-10的缺乏会导致肺部持续性炎症。我们最近报道了一种类似于骨髓源性抑制细胞（MDSC）的肺细胞类型的鉴定，该细胞响应于LPS而扩增，并通过IL-10的产生发挥免疫抑制功能。我们表明，这种细胞类型是总肺中IL-10的主要来源。那么，如果这种细胞类型提供的IL-10有助于解决炎症并在病原体感染后恢复体内平衡，为什么该程序有时会在肺炎中失败？我们已经确定了一种新的机制，其中心磷脂（CL），其水平显着增加，在肺炎患者的肺部，损害宿主免疫力通过抑制生产的抗炎细胞因子IL-10。CL与TLR 7相互作用并在MDSC样细胞中产生有效的PPARy拮抗剂环磷脂酸（cPA）。我们的研究结果使我们假设：1）由于CL和TLR 7之间的相互作用，CL被募集到吞噬溶酶体，其中磷脂酶02参与从CL产生cPA。2)cPA对PPARy活性的拮抗作用抑制IL-10的产生，从而损害细菌性肺炎消退中的抗炎机制。为了解决这些假设，我们将： 目标1.研究CL-TLR 7相互作用在CL抑制IL-10产生中的作用以及在IL-10产生中的作用。 调节细菌性肺炎。 目标二。研究在CL的存在下，使PLD 2失效或加强PPAR γ是否保留了来自肺髓样细胞的晚期IL-10产生。