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: 10526202
• 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/10526202
• 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; 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; Lead; Lectin; Leukocytes; Life; Ligands; Link; Low Density Lipoprotein Receptor; Lung; Mediating; Metabolic; Metabolic Pathway; Metabolism; Morbidity - disease rate; Mus; Neutrophil Infiltration; Obesity; Oxides; 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; macrophage; 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增长。 随着SARS-CoV2的大流行。肺炎的康复需要清除病原体和 感染的解决，后者是恢复正常肺功能的关键。虽然这两个进程都是 对宿主健康很重要，但对调节抗药性和抗药性的机制知之甚少。 肺炎期间组织损伤的解决，在我们对肺炎的认识上有很大的差距。 肺的生物学及其修复过程。在这里，我们提出了凝集素样氧化型低密度脂蛋白 受体-1(LOX-1)通过以下途径调节急性肺炎症 白细胞反应的重新编程。LOX-1是一种E类清道夫受体，主要因其在 在动脉粥样硬化过程中促进血管炎症。与之形成直接对比的是，我们的数据表明LOX-1具有 在肺中具有独特的功能，可防止肺水肿性损伤和炎症，不受细菌的影响 大肠埃希菌和肺炎链球菌肺炎小鼠模型的清除。此外，LOX-1 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LOX-1在肺组织中的细胞表达分析表明， 肺泡巨噬细胞和招募的中性粒细胞对LOX-1的表达具有独特的富集性。 造血细胞也可能是LOX-1依赖保护的来源，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，WT(LOX-1/-受体)嵌合体受到的保护明显更强。 对LOX-1抑制肺泡巨噬细胞的特异性影响的评估表明， 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，脂肪酸氧化降低，与炎性巨噬细胞一致。此外，我们 发现招募的中性粒细胞在LOX-1的表达上有所不同，其中大约一半的中性粒细胞是 在感染期间呈阳性。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，这可能是唯一促进组织分辨率的因素。加在一起， 白细胞是LOX-1的重要来源，可能对LOX-1的依赖保护起作用 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， 我们提出了一个中心假设，即LOX-1信号在白细胞中引发组织保护机制 (K99)，与炎症减轻和组织增加的代谢变化有关 恢复(R00)。我们的研究结果将第一次阐明LOX-1是如何在 在肺的独特微环境中的转录和代谢水平，在那里它可能促进 肺炎的康复和肺的动态平衡。