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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、恐怖主义和地缘政治不稳定带来了大量辐射暴露的风险。由于中性粒细胞在辐射暴露后显着下降，巨噬细胞承担清除大多数易位或入侵细菌的重要作用。但研究却很少评估了辐射对分化、非分裂组织居民吞噬功能的影响巨噬细胞。我们发现细胞外冷诱导RNA结合蛋白（eCIRP）是一种新型的可导致先天性免疫功能障碍的介质。在我们的初步研究中，我们已经表明体内和体外辐射暴露后 eCIRP 的释放增加。 CIRP 的缺陷改善了接受全身照射（TBI）的小鼠的存活率。脓毒症显着恶化了 TBI 后的生存率，但 CIRP-/- 小鼠的细菌载量较低，脓毒症后存活率提高，这表明 eCIRP 的有害影响可能是由于细菌清除受损所致。事实上，eCIRP 显着降低了巨噬细胞通过细胞骨架麻痹吞噬大肠杆菌。 eCIRP 还诱导了宏的形成噬菌体细胞外陷阱，细胞外陷阱减少了巨噬细胞对垂死细胞的吞噬作用。我们有确定髓样细胞 1 (TREM-1) 上表达的触发受体是 eCIRP 受体，并且 TREM-1 激活在 eCIRP 介导的巨噬细胞吞噬功能障碍中发挥着关键作用。而且， TREM-1-/- 小鼠 TBI 后 30 天的存活率显着提高。基于这些新颖的发现，我们假设电离辐射激活 TREM-1 后释放的 eCIRP，导致巨噬细胞吞噬细胞功能障碍，最终导致败血症和死亡。我们还表明，新的抑制剂 M3 减少了 eCIRP 与 TREM-1 的结合，并提高了脓毒症后的生存率。因此，我们进一步假设抑制 eCIRP/TREM-1 与 M3 的相互作用可恢复巨噬细胞的吞噬功能，从而提高单独遭受放射损伤或并发败血症的小鼠的存活率。在这个项目中，我们计划进一步确定 eCIRP 对辐射引起的巨噬细胞吞噬功能障碍的关键作用，确定 eCIRP 导致巨噬细胞吞噬功能障碍的机制，并将 M3 开发为针对 eCIRP 诱导的巨噬细胞吞噬功能障碍的新型放射医学对策。这些研究将为辐射诱导的先天免疫的发病机制提供新的机制见解功能障碍，以及针对有或没有严重辐射暴露的受害者的新医疗对策败血症。