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发挥着重要作用，其中中性粒细胞和巨噬细胞在其中发挥着重要作用。然而，在病原体清除之后，需要抑制中性粒细胞的流入并清除死亡的中性粒细胞，以尽量减少组织损伤。这种反应有时会在肺炎中受到损害，其中持续的中性粒细胞炎症会对肺组织造成附带损害，从而导致急性肺损伤。 IL-10 是一种重要的免疫抑制细胞因子，其中和或缺失已被证明会影响炎症的消退，这一点可以通过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​​总是有益的。在感染导致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 的存在会阻碍细菌清除。我们提出了我们的新观察结果，即感染后 IL-10 的缺失会导致肺部持续炎症。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 LPS 进行扩增，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 有助于解决病原体感染后的炎症并恢复体内平衡，为什么该程序有时会在肺炎中失败呢？我们发现了一种新机制，心磷脂 (CL) 在肺炎患者肺部的水平显着升高，通过抑制抗炎细胞因子 IL-10 的产生，损害宿主免疫力。 CL 与 TLR7 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做出假设：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 参与从 CL 生成 cPA。 2) cPA 拮抗 PPARγ 活性会抑制 IL-10 的产生，从而损害细菌性肺炎消退过程中的抗炎机制。为了解决这些假设，我们将： 目标 1. 研究 CL-TLR7 相互作用在 CL 抑制 IL-10 产生中的作用以及 调节细菌性肺炎。 目标 2. 研究在 CL 存在的情况下禁用 PLD2 或增强 PPARy 是否可以保留肺骨髓细胞的晚期 IL-10 产生。

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.