Establishing Mechanisms of LOX-1-Dependent Immune Regulation During Pneumonia

建立肺炎期间LOX-1依赖性免疫调节机制

基本信息

批准号：
10674622
负责人：
Filiz Korkmaz
金额：
$ 10.64万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10674622
关键词：
Acute Acute Respiratory Distress Syndrome Alveolar Macrophages Anticholesteremic Agents Atherosclerosis Bacteria Binding Biological Biology Blood Bronchoalveolar Lavage Fluid C-Type Lectins COVID-19 pandemic Cell Respiration Cells Cessation of life Chimera organism Cholesterol Homeostasis Curiosities Data Diabetes Mellitus Diagnosis Ensure Escherichia coli Exhibits Gene Expression Regulation Genes Genetic Transcription Glycolysis Health Hematopoietic Homeostasis Immune Immune response Immune signaling Infection Inflammation Inflammatory Injury Investigation Knockout Mice Knowledge LOX gene Lectin Leukocytes Life Ligands Link Low Density Lipoprotein Receptor Lung Macrophage Mediating Metabolic Metabolic Pathway Metabolism Morbidity - disease rate Mus Neutrophil Infiltration Obesity PTPRC gene Patients Phenotype Pilot Projects Pneumonia Predisposition Process Pulmonary Inflammation Recovery Research Resistance Resolution Role Signal Transduction Source Streptococcus pneumoniae Testing Tissues Training career cell type cholesterol biosynthesis fatty acid oxidation immune function immunoregulation in vivo insight lipid metabolism lung injury mortality mouse model multidisciplinary neutrophil oxidized low density lipoprotein pathogen prevent programs protective effect pulmonary function receptor density recruit repaired response scavenger receptor single-cell RNA sequencing small molecule inhibitor tissue injury tool vascular inflammation

项目摘要

Abstract Pneumonia is the leading cause of infection-related deaths worldwide, a fact that is set to rise exponentially with the SARS-CoV2 pandemic. Recovery from pneumonia requires both clearance of the pathogen and resolution of infection, the latter of which is critical to resume normal lung function. While both processes are important to host health, there is vastly less known about the mechanisms that regulate resistance to and resolution of tissue injury during pneumonia, representing a large knowledge gap in our understanding of the biology of the lung and its repair processes. Here, we propose that lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) modulates acute pulmonary inflammation in way that promotes resolution through reprogramming of leukocyte response. LOX-1 is a class E scavenger receptor, primarily known for its role in promoting vascular inflammation during atherosclerosis. In direct contrast, our data suggests that LOX-1 has a unique function in the lung, where it prevents edematous lung injury and inflammation, independent of bacterial clearance in murine models of Escherichia coli and Streptococcus pneumoniae pneumonia. Moreover, LOX-1 and its major ligand oxidized low-density lipoprotein (oxLDL) are elevated in patients with ARDS as a result of a confirmed diagnosis of pneumonia. Analysis of the cellular expression of LOX-1 in the lung revealed that alveolar macrophages and recruited (airspace) neutrophils are uniquely enriched for LOX-1 expression. Hematopoietic cells are also likely sources of LOX-1-dependent protection, as LOX-1-/- (WT recipient) chimeras are significantly more protected from injury than WT (LOX-1-/- recipient) chimeras during pneumonia. Assessment of the specific effects of LOX-1 inhibition on alveolar macrophages demonstrated that with inhibition macrophages are skewed towards inflammation and exhibit metabolic changes associated with increased glycolysis and lower fatty acid oxidation consistent with inflammatory macrophages. Moreover, we discovered that recruited neutrophils differ in their expression of LOX-1, where about half of neutrophils are positive during infection. Curiously, we also found phenotypic differences associated with LOX-1+ neutrophils that suggest increased cholesterol metabolism, which may uniquely promote tissue resolution. Taken together, leukocytes are an important source of LOX-1 and are likely responsible for LOX-1-dependent protection during pneumonia. However, whether and how LOX-1 elicits its protective effects on leukocytes is not known. Thus, we propose a central hypothesis that LOX-1 signaling evokes tissue-protective mechanisms in leukocytes (K99), that are associated with metabolic changes consistent with reduced inflammation and increased tissue recovery (R00). Results from our investigations will be the first to elucidate how LOX-1 is regulated at the transcriptional and metabolic level in the unique microenvironment of the lung, where it likely facilitates recovery from pneumonia and lung homeostasis.

抽象的肺炎是全球感染相关死亡的主要原因，这一事实将呈指数级增长随着 SARS-CoV2 大流行。肺炎的康复需要清除病原体和感染的解决，后者对于恢复正常的肺功能至关重要。虽然这两个过程都是对宿主健康很重要，但人们对调节抵抗力和抵抗力的机制知之甚少。肺炎期间组织损伤的解决，代表着我们对肺炎的理解存在巨大的知识差距肺的生物学及其修复过程。在这里，我们提出凝集素样氧化低密度脂蛋白受体 1 (LOX-1) 通过促进消退的方式调节急性肺部炎症白细胞反应的重新编程。 LOX-1 是一种 E 类清道夫受体，主要以其在促进动脉粥样硬化期间的血管炎症。与此形成鲜明对比的是，我们的数据表明 LOX-1 具有在肺部具有独特的功能，可防止水肿性肺损伤和炎症，不受细菌的影响在大肠杆菌和肺炎链球菌肺炎的小鼠模型中清除。此外，LOX-1 由于以下原因，ARDS 患者中其主要配体氧化低密度脂蛋白 (oxLDL) 升高确诊为肺炎。对肺中 LOX-1 细胞表达的分析表明肺泡巨噬细胞和招募的（空域）中性粒细胞具有独特的 LOX-1 表达富集。造血细胞也可能是 LOX-1 依赖性保护的来源，如 LOX-1-/-（WT 受体）嵌合体在肺炎期间，它们比 WT（LOX-1-/- 受体）嵌合体更能免受损伤。 LOX-1 抑制对肺泡巨噬细胞的具体影响的评估表明，抑制巨噬细胞偏向炎症并表现出与以下相关的代谢变化糖酵解增加和脂肪酸氧化降低，与炎症巨噬细胞一致。此外，我们发现招募的中性粒细胞的 LOX-1 表达有所不同，其中大约一半的中性粒细胞感染期间呈阳性。奇怪的是，我们还发现了与 LOX-1+ 中性粒细胞相关的表型差异这表明胆固醇代谢增加，这可能独特地促进组织溶解。综合起来，白细胞是 LOX-1 的重要来源，可能负责 LOX-1 依赖性保护肺炎。然而，LOX-1 是否以及如何对白细胞产生保护作用尚不清楚。因此，我们提出一个中心假设，即 LOX-1 信号传导会引发白细胞的组织保护机制 (K99)，与代谢变化相关，与减少炎症和增加组织一致恢复（R00）。我们的调查结果将首次阐明 LOX-1 在肺部独特的微环境中的转录和代谢水平，可能有助于从肺炎中恢复和肺稳态。