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：
10474023
负责人：
Monowar Aziz
金额：
$ 72.66万
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/10474023
关键词：
Actins Acute Affect Attenuated Bacteria Bacterial Counts Bacterial Infections Binding Binding Proteins Blood Cause of Death Cells Cessation of life Cytoskeletal Modeling Cytoskeletal Proteins 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 Knockout Mice Kupffer Cells Mediating Mediator of activation protein 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 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 base extracellular gain of function improved in vivo inhibitor insight loss of function macrophage 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大规模辐射暴露的风险。随着嗜中性粒细胞明显降低辐射暴露，巨噬细胞假定去除大多数易位或入侵细菌的重要作用。但是，很少有研究已经评估了辐射对分化，非分散组织居民的吞噬功能的影响巨噬细胞。我们发现细胞外冷诱导的RNA结合蛋白（ECIRP）是一种新颖可能引起先天免疫功能障碍的介体。在我们的初步研究中，我们显示了在体内和体外暴露后ECIRP的释放增加。 CIRP的不足改善了受全身辐照（TBI）的小鼠的存活。败血症显着恶化了TBI生存，但是CIRP - / - 小鼠的细菌负荷较低，败血症后的生存率提高，这表明ECIRP 有害效应可能是由于细菌清除率受损所致。确实，ECIRP大大减少了大肠杆菌通过细胞骨架瘫痪的巨噬细胞吞噬作用。 ECIRP还诱导了宏的形成噬菌体细胞外陷阱和细胞外陷阱减少了垂死细胞的巨噬细胞吞噬作用。我们有确定在髓样细胞1（trem-1）上触发受体是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起关键作用。而且，在TREM-1/ - 小鼠中，TBI后的30天生存率显着提高。基于这些新颖的发现，我们假设在电离辐射后释放的ECIRP激活了TREM-1，导致巨噬细胞吞噬功能障碍，最终导致败血症和死亡。我们还表明了新的抑制剂 M3降低了ECIRP与TREM-1的结合，并改善了败血症后的生存率。因此，我们进一步假设抑制ECIRP/TREM-1与M3的相互作用恢复了巨噬细胞的吞噬功能，从而恢复了改善单独受辐射损伤或败血症复杂的小鼠的存活。在这个项目中，我们计划进一步建立ECIRP在辐射诱导的巨噬细胞功能障碍中的关键作用，确定ECIRP引起巨噬细胞吞噬功能障碍的机制，并形成M3作为A 靶向ECIRP诱导的巨噬细胞功能障碍的新型辐射医学对策。这些研究应提供有关辐射诱导的先天免疫发病机理的新机械见解功能障碍，以及带有或不带有重大辐射暴露的惊喜的新医疗对策败血症。