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: 10451112
• 负责人: Marcelo G Bonini
• 金额: $ 57.08万
• 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/10451112
• 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; Lead; Licensing; Lung; Lung infections; 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; Prevalence; Prevention; Production; Promoter Regions; Publishing; Pulmonary Inflammation; Pulmonology; Reactive Oxygen Species; Regulatory Element; Research; Resolution; Risk; Role; SWI1; Signal Transduction; Smoker; Smoking; Speed; Sterility; Structure of parenchyma of lung; TNFRSF5 gene; Testing; Therapeutic; Tissues; bactericide; base; catalase; experience; fighting; gene network; genomic locus; healing; human old age (65+); inhibitor; injury and repair; knockout animal; lung injury; macrophage; monocyte; mortality; mouse model; neutrophil; novel; oxidation; p65; pathogenic microbe; preservation; prevent; promoter; recruit; response; surfactant production; tissue injury; 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 该应用是基于发现活性氧和氮种（Rons）的发现 在巨噬细胞的核中是强大的信号，以衡量早期的极化 免疫反应，尤其是炎症急性相的激活。 具体而言，我们发现促炎性NFκB-target基因的子集的启动子， 虽然保持始终可访问，但与SOCS1的关联使氧化还原敏感 结合并耗尽传入的p65NFκB的蛋白质。这种机制只是阻止 稳态期间的炎症组织损伤以及提供快速而特定的途径 动员侵略性的先天免疫细胞狩猎和杀死高度增殖的致病性 微生物。 NOS1衍生的一氧化氮（NO）通过S-硝基化许可取代SOCS1 急性促炎NFκB-target基因的转录。因为H2O2（ROS）可以修改 半胱氨酸与NO类似，我们假设细胞核中的氧化应激模仿NO， 将SOCS1置于促炎基因的调节区域，并防止其DE Novo沉积，从而扩大了急性炎症并防止过渡 炎症分辨率和组织愈合。临床上，这种加剧了肺组织损伤 并提高了由老年引起的潜在氧化应激患者的ARD风险， 吸烟，自身免疫或其他情况。有趣的是，我们发现虽然压制 核NO或ROS消除了大部分炎症组织损伤，响应LPS， 小鼠控制K.肺炎感染的能力保持完整，表明针对核 没有现有化合物的NO和ROS可能在临床上可以防止高危患者 演变成ards。目前，预防和管理是通过使用 强大的免疫抑制药物会损害患者对抗感染的能力。在 在这方面，这个提议的项目有可能在该领域迈出长期的SCART目标 正在寻找抑制炎症组织损伤和ARD的方法，同时保持 先天免疫细胞以消除感染剂完整。