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.

抽象的 肺炎是全球与感染有关的死亡的主要原因，这一事实将成倍增长 与SARS-COV2大流行有关。从肺炎中恢复需要清除病原体和 感染的分辨率，后者对于恢复正常的肺功能至关重要。虽然两个过程是 对托管健康很重要，对调节对和抗药性的机制众所周知 解决肺炎期间组织损伤的分辨率，代表了我们对 肺的生物学及其修复过程。在这里，我们建议凝集素样氧化的低密度脂蛋白 受体1（LOX-1）以方式调节急性肺部炎症，从而促进通过 重编程白细胞反应。 LOX-1是E类清除剂受体，主要以其在其中的作用而闻名 在动脉粥样硬化期间促进血管炎症。相比之下，我们的数据表明LOX-1具有 肺部独特功能，在肺部防止水肿肺损伤和炎症，与细菌无关 大肠杆菌和肺炎链球菌的鼠模型中的清除。此外，LOX-1 ARDS患者的主要配体氧化低密度脂蛋白（OXLDL）升高 确认的肺炎诊断。对肺中LOX-1的细胞表达的分析表明， 肺泡巨噬细胞和招募的（空域）中性粒细胞在LOX-1表达中独特地富集。 造血细胞也可能是LOX-1依赖性保护的来源，如Lox-1 - / - （WT接收者）嵌合体 肺炎期间，比WT（LOX-1 - / - 受体）嵌合体更受损伤的保护。 评估LOX-1抑制对肺泡巨噬细胞的特定影响表明， 抑制巨噬细胞倾向于炎症，并表现出与 与炎症巨噬细胞一致的糖酵解和较低的脂肪酸氧化。而且，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 感染期间阳性。奇怪的是，我们还发现与Lox-1+中性粒细胞相关的表型差异 这表明增加了胆固醇代谢，这可能会独特地促进组织分辨率。在一起， 白细胞是LOX-1的重要来源，很可能是由LOX-1依赖的保护 肺炎。但是，尚不清楚LOX-1是否以及如何引起其对白细胞的保护作用。因此， 我们提出了一个中心假设，即LOX-1信号传导唤起白细胞中的组织保护机制 （K99），与代谢变化有关，与炎症减少和组织增加有关 恢复（R00）。我们的调查结果将是第一个阐明如何调节LOX-1的结果 在独特的肺微环境中的转录和代谢水平，可能会促进它 从肺炎和肺稳态中恢复。