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中的病原体方面起着至关重要的作用，其中中性粒细胞和巨噬细胞都起着重要的作用。然而，在病原体清除后，需要抑制中性粒细胞的流入，并清除死亡的中性粒细胞，以将组织损害降至最低。这种反应在肺炎中有时会受到损害，在肺炎中，持续的中性粒细胞炎症会对肺组织造成附带损害，导致急性肺损伤。IL-10是一种重要的免疫抑制细胞因子，其中和或缺失影响炎症的消退，表现为多种病原体感染后的持续性免疫病理损伤。然而，在病原体感染期间，IL-10并不总是有益的。在感染导致院内肺炎的革兰氏阴性杆菌肺炎后的早期时间点，发现IL-10的存在阻碍了细菌的清除。我们提出了我们的新观察结果，即感染后后期缺乏IL-10会导致肺部持续炎症。我们最近报道了一种类似于髓系抑制细胞(MDSCs)的肺细胞类型，它能在内毒素的作用下扩张，并通过产生IL-10发挥免疫抑制功能。我们证明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化解炎症和恢复动态平衡，为什么该计划有时在肺炎中失败？我们发现了一种新的机制，通过抑制抗炎细胞因子IL-10的产生，心磷脂(CL)在肺炎患者的肺部水平显著增加，从而损害宿主免疫。CL与TLR7相互作用，在类MDSC细胞中产生强有力的PPARy拮抗剂环磷脂酸(CPA)。我们的发现使我们假设：1)由于CL与TLR7之间的相互作用，CL被招募到吞噬溶酶体中，其中磷脂酶02参与了CL生成CPA的过程。2)CPA拮抗PPARy活性可抑制IL-10的产生，从而影响细菌性肺炎的抗炎机制。为了解决这些假设，我们将： 目的1.研究CL-TLR7相互作用在CL和In抑制IL-10产生中的作用 调节细菌性肺炎。 目的2.研究在CL存在的情况下，禁用PLD2或增强PPARy是否保留了肺髓系细胞产生的晚期IL-10。

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.