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.

总结 该应用基于活性氧和氮物质（RONS） 在巨噬细胞的细胞核内是调节早期细胞极化的强大信号。 免疫应答，特别是炎症急性期的激活。 具体来说，我们发现促炎性NFκ B靶基因的启动子， 虽然保持组成型可接近，但通过与SOCS 1，氧化还原敏感的 结合并消耗传入p65 NFκB的蛋白质。该机制同时防止 炎症组织损伤在稳态以及提供了一个快速和具体的途径 动员攻击性先天免疫细胞来猎杀高度增殖性病原体 微生物NOS 1衍生的一氧化氮（NO）通过S-亚硝基化取代SOCS 1， 急性促炎性NFκ B靶基因的转录。因为H2 O2（ROS）可以修饰 半胱氨酸类似于NO，我们假设细胞核中的氧化应激模拟NO， 将SOCS 1从促炎基因的调控区中置换出来，并阻止其降解， 新生沉积，从而延长炎症的急性期并防止转化 炎症消退和组织愈合。临床上，这会加重肺组织损伤 并增加了老年引起的潜在氧化应激患者的ARDS风险， 吸烟、自身免疫或其他疾病。有趣的是，我们发现，尽管抑制了 核内NO或ROS消除了大部分响应于LPS的炎性组织损伤， 小鼠控制K.肺炎感染保持完整，表明靶向核 NO和ROS与现有的化合物可能是临床上有用的，以防止风险患者 发展成ARDS。目前，ARDS的预防和管理是通过使用 强效免疫抑制药物，损害患者抵抗感染的能力。在 在这方面，本拟议项目有可能推进该领域长期追求的目标， 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，以消除感染原完好无损。