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.

概括 该应用基于活性氧和氮物种 (RONS) 的发现 巨噬细胞核内有强大的信号调节早期巨噬细胞的极化 免疫反应，特别是炎症急性期的激活。 具体来说，我们发现促炎 NFκB 靶基因子集的启动子， 在保持组成型可及性的同时，通过与氧化还原敏感的 SOCS1 关联而被抑制 结合并消耗传入的 p65 NFκB 的蛋白质，此机制可同时防止。 稳态期间的炎症组织损伤，并提供快速且特定的途径 动员侵略性的先天免疫细胞来捕猎和杀死高度增殖的病原体 NOS1 衍生的一氧化氮 (NO) 通过 S-亚硝基化许可取代 SOCS1。 因为 H2O2 (ROS) 可以修饰急性促炎性 NFκB 靶基因的转录。 半胱氨酸与 NO 类似，我们发现细胞核中的氧化应激类似于 NO， 取代 SOCS1 对促炎基因的调节并防止其消失 新沉积从而延长炎症的急性期并阻止转变 临床上，这会加重肺组织损伤。 并增加因老年引起的潜在氧化应激的患者患 ARDS 的风险， 吸烟、自身免疫或其他疾病。 核 NO 或 ROS 消除了 LPS 引起的大部分炎症组织损伤， 小鼠控制肺炎克雷伯菌感染的能力保持完整，表明靶向核 NO 和 ROS 与现有化合物在临床上可能有助于预防高危患者 目前，ARDS 的预防和管理是通过使用 强效免疫抑制药物会损害患者抵抗感染的能力。 在这方面，该拟议项目有可能推动该领域长期追求的目标： 正在寻找抑制炎症组织损伤和 ARDS 的方法，同时保留 先天免疫细胞可以完整地消除感染因子。