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

• 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
• 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

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.

摘要 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上升 SARS冠状病毒2型大流行从肺炎中恢复需要清除病原体， 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 对于宿主健康很重要，但人们对调节对 肺炎期间组织损伤的解决，代表了我们对肺炎的理解存在很大的知识差距。 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）调节急性肺部炎症的方式，通过 白细胞反应的重编程。LOX-1是一种E类清道夫受体，主要以其在细胞凋亡中的作用而闻名。 在动脉粥样硬化期间促进血管炎症。与此形成鲜明对比的是，我们的数据表明，LOX-1具有一个 在肺中具有独特的功能，它可以防止水肿性肺损伤和炎症，不依赖于细菌 大肠杆菌和肺炎链球菌肺炎的小鼠模型中的清除率。此外，LOX-1 及其主要配体氧化低密度脂蛋白（oxLDL）在ARDS患者中升高， 确诊为肺炎对肺中LOX-1的细胞表达的分析显示， 肺泡巨噬细胞和募集的（气隙）嗜中性粒细胞独特地富集LOX-1表达。 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，与WT（LOX-1-/-受体）嵌合体相比， LOX-1抑制对肺泡巨噬细胞的特异性作用的评估表明， 抑制巨噬细胞倾向于炎症，并表现出与炎症相关的代谢变化。 糖酵解增加和脂肪酸氧化降低与炎性巨噬细胞一致。而且我们 发现募集的中性粒细胞在LOX-1的表达上存在差异，其中大约一半的中性粒细胞是 感染时呈阳性。奇怪的是，我们还发现LOX-1+中性粒细胞的表型差异 这表明胆固醇代谢增加，这可能独特地促进组织消退。综合起来看， 白细胞是LOX-1的重要来源，并且可能负责LOX-1依赖性保护， 肺炎然而，LOX-1是否以及如何发挥其对白细胞的保护作用尚不清楚。因此，在本发明中， 我们提出了一个中心假设，即LOX-1信号转导引起白细胞的组织保护机制 (K99)，这与代谢变化有关，与炎症减少和组织增加一致 回收率（R 00）。我们的研究结果将首次阐明LOX-1是如何调节的， 转录和代谢水平在肺的独特微环境中，在那里它可能促进 从肺炎和肺内环境稳定中恢复。