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Mechanisms of Radiation-Induced Innate Immune Dysfunction and Its Countermeasures

辐射引起的先天性免疫功能障碍的机制及对策

基本信息

批准号：
10669714
负责人：
Monowar Aziz
金额：
$ 75.19万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-21 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669714
关键词：
Actins Acute Affect Bacteria Bacterial Counts Bacterial Infections Binding Binding Proteins Blood Cause of Death Cells Cessation of life Cytoskeletal Modeling Cytoskeletal Proteins Cytoskeleton Defect Dose Drug Kinetics Escherichia coli Excision Exposure to FDA approved Filgrastim Filopodia Greater sac of peritoneum Human Immune System Diseases Immune response Impairment In Vitro Infection Infection Control Invaded Ionizing radiation Knock-out Kupffer Cells Macrophage Mediating Mediator Molecular Mus Myeloid Cells Nuclear power plant accident Paralysed Pathogenesis Pathway interactions Pattern Peptide Hydrolases Peritoneal Macrophages Peroxidases Persons Phagocyte Bactericidal Dysfunction Phagocytes Phagocytosis Play Polymers Proteins Proteomics RNA-Binding Proteins Radiation Radiation Dose Unit Radiation Injuries Radiation exposure Risk Role STAT1 protein Sepsis Severities Stat3 protein Terrorism Therapeutic Time Tissues Toxicology Whole-Body Irradiation Wild Type Mouse extracellular gain of function improved in vivo inhibitor insight loss of function medical countermeasure mesenteric lymph node neutrophil novel novel therapeutics polymerization protein activation public health relevance radiation effect receptor restoration

项目摘要

PROJECT DESCRIPTION: Nuclear power plant accidents, terrorism, and geopolitical instability present the risk of massive radiation exposure. As neutrophils markedly decline post-radiation exposure, macrophages assume the important role of removing most translocated or invading bacteria. However, very few studies have evaluated the effects of radiation on the phagocytic function of differentiated, non-dividing tissue resident macrophages. We have discovered that extracellular cold-inducible RNA-binding protein (eCIRP) is a novel mediator which can cause innate immune dysfunction. In our preliminary studies, we have shown an increased release of eCIRP after radiation exposure in vivo and in vitro. Deficiency in CIRP improved the survival of mice subjected to total body irradiation (TBI). Sepsis significantly worsened the survival post-TBI, but CIRP-/- mice had lower bacterial loads and improved survival after sepsis, suggesting that eCIRP’s detrimental effect may be due to the impaired bacterial clearance. Indeed, eCIRP significantly reduced macrophage phagocytosis of E. coli via cytoskeletal paralysis. eCIRP also induced the formation of macro- phage extracellular traps, and extracellular traps reduced macrophage phagocytosis of dying cells. We have identified that triggering receptor expressed on myeloid cells-1 (TREM-1) is the eCIRP receptor, and that TREM-1 activation plays a critical role in the eCIRP-mediated macrophage phagocytic dysfunction. Moreover, the 30-day survival after TBI was significantly improved in TREM-1-/- mice. Based on these novel findings, we hypothesize that eCIRP released after ionizing radiation activates TREM-1, resulting in macrophage phagocytic dysfunction and ultimately leading to sepsis and death. We have also shown that the new inhibitor M3 reduced eCIRP’s binding to TREM-1 and improved survival after sepsis. As such, we further hypothesize that inhibition of eCIRP/TREM-1 interaction with M3 restores macrophage phagocytic function, thereby improving the survival of mice subjected to radiation injury alone or complicated by sepsis. In this project, we plan to further establish the critical role of eCIRP on radiation-induced macrophage phagocytic dysfunction, determine the mechanisms by which eCIRP causes macrophage phagocytic dysfunction, and develop M3 as a novel radiation medical countermeasure targeting eCIRP-induced macrophage phagocytic dysfunction. These studies shall provide novel mechanistic insights into the pathogenesis of radiation-induced innate immune dysfunction, as well as a new medical countermeasure for victims of major radiation exposure with or without sepsis.

项目描述：核电站事故、恐怖主义、地缘政治不稳定等问题