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.

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