LncRNA regulates lung inflammation

LncRNA调节肺部炎症

• 批准号: 10205157
• 负责人: Yang Jin
• 金额: $ 49.16万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205157
• 关键词: Alveolar; Alveolar Macrophages; Antibiotic Resistance; Antisense Oligonucleotides; Bacteria; Bacterial Infections; Bacterial Pneumonia; Cause of Death; Cell model; Cells; Code; Computer Models; Control Groups; Data; Development; Edema; Epithelial Cells; Escherichia coli; Exhibits; Exposure to; Future; Genes; Genetic Transcription; Homologous Gene; Host Defense; Human; Human Genome; Immune; In Vitro; Infection; Infiltration; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Klebsiella pneumoniae; Leukocytes; Lung; Lung Inflammation; Lung diseases; Lung infections; Macrophage Activation; Mediating; Methods; Morbidity - disease rate; Mus; Natural Immunity; Nucleotides; Pathogenesis; Proteins; Public Health; Publishing; RNA Sequences; Regulation; Research; Role; System; Testing; Therapeutic; Tissues; Transcript; United States; Untranslated RNA; Work; bactericide; base; body system; chemokine; clinically significant; cytokine; exosome; gain of function; in vivo; in vivo Model; innovation; insight; macrophage; mortality; mouse model; neutrophil; new therapeutic target; novel; pathogenic microbe; programs; response; therapeutic target

ABSTRACT Lung infections place a major burden on public health worldwide and are the leading cause of death in the United States. Infections caused by gram-negative (G-) bacteria have features that are of particular concern, such as being highly efficient at acquiring antibiotic resistance. Alveolar macrophages (AMs) form the first line of defense in lungs toward microbial pathogens via protective inflammatory responses. The high mortality and morbidity after bacterial infection often result from an imbalance in host defense between bactericidal and an excessive inflammatory response that leads to tissue damage. Despite years of research, the initiation, propagation and regulation of inflammatory lung responses in the presence of G- bacterial infection remains incompletely explored. Only recently has it been recognized that long non-coding RNAs (lncRNA) are extensively expressed in various immune cells including the macrophages, but very little has been known about their functional roles. We screened lncRNA expressions in mouse lungs after intra-tracheal instillation of LPS, Klebsiella pneumoniae (K.pneumoniae) and Escherichia coli (E.coli). LncRNA lincenc1 exhibited the greatest induction in expression among treated groups. Functionally, lincenc1 promotes the classical activation (M1) of macrophages and the secretion of pro-inflammatory cytokines. Deletion of lincenc1 in AMs using the specific antisense oligonucleotides (ASO) in vivo significantly reduces the LPS-induced leukocyte infiltration and alveolar edema, when compared with the control group. Furthermore, inhibition of lincenc1 using ASO down-regulates multiple inflammatory cytokines and chemokines (Il-1β, Il-6, Cxcl1 and Cxcl2), detected in BALF after exposure to LPS. Mechanistically, we found that lincenc1 co-localizes with NLRP3 components in the presence of LPS, suggesting a regulatory role of lincenc1 on NLRP3 inflammasone activation. Based on our published and preliminary data, our central hypothesis is that lncRNA lincenc1 facilitates G-bacteria/LPS induced lung inflammation via promoting classical activation of macrophages through NLRP3 inflammasome assembly and activation. We propose three specific aims: Specific Aim I: To determine the role of lncRNA lincenc1 in macrophage activation in vitro. Specific Aim II: To determine the role of lincenc1 in lung inflammation in vivo. Specific Aim III: To determine whether lincenc1 serves as a potential therapeutic target in vivo.

摘要 肺部感染给全世界的公共卫生带来了重大负担，并且是世界上主要的死亡原因。 美国的由革兰氏阴性（G-）细菌引起的感染具有特别令人关注的特征， 例如在获得抗生素抗性方面非常有效。肺泡巨噬细胞（AM）形成第一线 肺通过保护性炎症反应防御微生物病原体。高死亡率和 细菌感染后的发病率通常是由于宿主在杀菌和抗细菌之间的防御失衡造成的。 导致组织损伤的过度炎症反应。尽管经过多年的研究， 在G-细菌感染的情况下，炎症性肺反应的传播和调节仍然存在 不完全探索。直到最近才认识到长链非编码RNA（lncRNA）是 在包括巨噬细胞在内的各种免疫细胞中广泛表达，但对 他们的职能作用。我们筛选了气管内滴注LPS后小鼠肺中lncRNA的表达， 肺炎克雷伯菌（肺炎克雷伯菌）和大肠埃希菌（大肠埃希菌）。LncRNA lincenc 1表现出最大的 在处理组中诱导表达。在功能上，lincenc 1促进经典激活（M1）， 巨噬细胞和促炎细胞因子的分泌。使用特定的 体内反义寡核苷酸（阿索）可显着减少脂多糖诱导的白细胞浸润和肺泡炎 水肿，与对照组相比。此外，使用阿索抑制lincenc 1下调了 暴露后BALF中检测到多种炎性细胞因子和趋化因子（IL-1β、IL-6、Cxcl 1和Cxcl 2） 到LPS。从机制上讲，我们发现lincenc 1在LPS存在下与NLRP 3组分共定位， 提示lincenc 1对NLRP 3炎性因子激活的调节作用。根据我们发布的和 初步数据，我们的中心假设是lncRNA lincenc 1促进G-细菌/LPS诱导的肺 通过NLRP 3炎性体组装促进巨噬细胞的经典活化， activation.我们提出了三个具体目标：具体目标I：确定lncRNA lincenc 1在 体外巨噬细胞活化。具体目的II：确定lincenc 1在体内肺部炎症中的作用。 具体目标III：确定lincenc 1是否作为体内潜在的治疗靶点。