Dysregulation of Innate Immune response in Bacterial Pneumonia by Cardiolipin

宿主的先天免疫系统在清除肺部和其他器官的病原体中起着至关重要的作用，其中嗜中性粒细胞和巨噬细胞都起着重要作用。然而，在病原体清除后，中性粒细胞的流入需要被抑制，死亡的中性粒细胞需要被清除，以尽量减少组织损伤。这种反应有时在肺炎中受到损害，其中持续的中性粒细胞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，其中和或缺失已被证明影响炎症的消退，这在多种病原体感染后观察到持续的免疫病理损伤。然而，在病原体感染期间，IL-10并不总是有益的。在感染引起院内肺炎的革兰氏阴性细菌肺炎克雷伯菌后的早期时间点，发现IL-10的存在阻碍了细菌的清除。我们提出了新的观察结果，即感染后缺乏IL-10会导致肺部持续炎症。我们最近报道了一种类似髓源性抑制细胞（MDSCs）的肺细胞类型的鉴定，这种细胞在LPS的作用下扩张，并通过产生IL-10发挥免疫抑制功能。我们发现这种细胞类型是全肺中IL-10的主要来源。那么，如果这种细胞类型提供的IL-10有助于在病原体感染后解决炎症并恢复体内平衡，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，通过这种机制，心磷脂（CL）的水平在肺炎患者的肺部显着增加，通过抑制抗炎细胞因子IL-10的产生来损害宿主免疫。在mdsc样细胞中，CL与TLR7相互作用并产生强效的pparty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TLR7之间的相互作用，CL被招募到吞噬溶酶体，其中磷脂酶02参与了CL产生cPA的过程。2) cPA对pparty活性的拮抗作用抑制IL-10的产生，影响细菌性肺炎的抗炎机制。为了解决这些假设，我们将：

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.