A redox-sensitive switch in the macrophage nucleus regulates acute phase inflammatory injury

巨噬细胞核中的氧化还原敏感开关调节急性期炎症损伤

• 批准号: 10631088
• 负责人: Marcelo G Bonini
• 金额: $ 55.58万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631088
• 关键词: Acute; Acute Respiratory Distress Syndrome; Affect; Alveolar; Anti-Inflammatory Agents; Antioxidants; Autoimmunity; Bacteria; Bacterial Pneumonia; Binding Proteins; CISH gene; Cell Nucleus; Cells; ChIP-seq; Clinical; Confocal Microscopy; Critical Illness; Cysteine; Data; Deposition; Development; Diffuse; Elderly; Environment; Epigenetic Process; Equilibrium; Gene Targeting; Genes; Genetic Engineering; Genetic Transcription; Goals; Homeostasis; Hydrogen Peroxide; Immune; Immune response; Immunosuppressive Agents; Infection; Infectious Agent; Inflammation; Inflammatory; Injury; Klebsiella pneumoniae; Knock-in Mouse; Licensing; Lung; Lung infections; Macrophage; Mediating; Metabolic; Metabolic syndrome; Modeling; Modification; Molecular; Mus; Neutrophil Activation; Nitric Oxide; Nitric Oxide Synthase Type I; Nitrogen; Nuclear; Nucleic Acid Regulatory Sequences; Output; Overweight; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathway interactions; Patients; Phase; Phenotype; Pneumonia; Population; Predisposition; Prevalence; Prevention; Production; Promoter Regions; Publishing; Pulmonary Inflammation; Pulmonology; Reactive Oxygen Species; Regulatory Element; Research; Resolution; Risk; Role; SWI1; Signal Transduction; Smoker; Smoking; Specific qualifier value; Speed; Sterility; Structure of parenchyma of lung; TNFRSF5 gene; Testing; Therapeutic; Tissues; bactericide; catalase; experience; fighting; gene network; genomic locus; healing; human old age (65+); inhibitor; knockout animal; lung injury; monocyte; mortality; mouse model; neutrophil; novel; oxidation; p65; pathogenic microbe; preservation; prevent; promoter; recruit; response; surfactant production; tissue injury; tissue repair; transcription factor; ubiquitin-protein ligase

SUMMARY This application is based on the discovery that reactive oxygen and nitrogen species (RONS) within the nucleus of macrophages are powerful signals regulating the polarization of the early immune response and, in particular, the activation of the acute phase of inflammation. Specifically, we found that the promoters of a subset of pro-inflammatory NFκB-target genes, while remaining constitutively accessible, are muted by association with SOCS1, a redox sensitive protein that binds and depletes incoming p65 NFκB. This mechanism simultaneously prevents inflammatory tissue injury during homeostasis as well as provides a rapid and specific pathway to mobilizing aggressive innate immune cells to hunt and kill highly proliferative pathogenic microbes. NOS1-derived nitric oxide (NO) displaces SOCS1 by S-nitrosylation licensing the transcription of acute pro-inflammatory NFκB-target genes. Because H2O2 (ROS) can modify cysteines similarly to NO, we hypothesize that oxidative stress in the nucleus mimics NO, displacing SOCS1 from regulatory regions of pro-inflammatory genes as well as preventing its de novo deposition thereby extending the acute phase of inflammation and preventing the transition to inflammatory resolution and tissue healing. Clinically, this exacerbates pulmonary tissue injury and elevates the risk of ARDS in patients with underlying oxidative stress caused by old age, smoking, autoimmunity, or other conditions. Interestingly, we found that although suppressing nuclear NO or ROS eliminates much of the inflammatory tissue injury in response to LPS, the ability of mice to control K. pneumoniae infection remains intact, indicating that targeting nuclear NO and ROS with existing compounds may be clinically useful to prevent at-risk patients from evolving to ARDS. Currently, ARDS prevention and management is accomplished by the use of powerful immunosuppressive drugs that compromise the ability of the patient to fight infection. In this regard, this proposed project has the potential to advance a long sought goal in the field that is finding ways to suppress inflammatory tissue injury and ARDS while preserving the ability of innate immune cells to eliminate infectious agents intact.

摘要 这一应用是基于发现活性氧和氮物种(RON) 在巨噬细胞的核内有强大的信号调节早期的极化 免疫反应，特别是炎症急性期的激活。 具体地说，我们发现促炎因子κB靶基因的一个子集的启动子， 虽然在结构上保持可访问，但由于与氧化还原敏感的SOCS1结合而减弱 结合并消耗传入的p65 nFκB的蛋白质。这一机制同时阻止了 炎症组织损伤在动态平衡中的作用以及提供一种快速和特异的途径 动员攻击性先天免疫细胞追捕并杀死高增殖性病原体 微生物。NOS1衍生的一氧化氮(NO)用S取代SOCS1-亚硝化许可 急性促炎因子κB靶基因的转录。因为过氧化氢(ROS)可以改变 半胱氨酸与NO类似，我们假设细胞核中的氧化应激模仿NO， 使SOCS1从促炎基因的调控区移位并防止其变性 新星沉积从而延长了炎症的急性期并阻止了过渡 炎症消退和组织愈合。临床上，这会加重肺组织损伤。 并增加老年引起的潜在氧化应激患者患ARDS的风险， 吸烟、自身免疫力或其他情况。有趣的是，我们发现尽管压制 核一氧化氮或ROS消除了内毒素引起的大部分炎性组织损伤， 小鼠控制肺炎克雷伯菌感染的能力保持不变，表明靶向核 NO和ROS与现有化合物一起可能在临床上用于预防高危患者 演变为急性呼吸窘迫综合征。目前，ARDS的预防和管理是通过使用 强大的免疫抑制药物，损害患者抵抗感染的能力。在……里面 在这方面，这一拟议项目有可能推进该领域长期寻求的目标 正在寻找抑制炎性组织损伤和ARDS的方法，同时保留 先天免疫细胞能完好无损地消灭感染性病原体。