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

• 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
• 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

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。由于中性粒细胞在辐射暴露后显著下降， 承担去除大多数移位或入侵细菌的重要作用。然而，很少有研究 已经评估了辐射对分化的、非分裂的组织驻留细胞的吞噬功能的影响， 巨噬细胞我们已经发现细胞外冷诱导RNA结合蛋白（eCIRP）是一种新的 可导致先天性免疫功能障碍的介质。在我们的初步研究中， 体内和体外辐射暴露后eCIRP的释放增加。CIRP的不足改善了 接受全身照射（TBI）的小鼠的存活率。脓毒症显著恶化了TBI后的生存率， 但CIRP-/-小鼠的细菌负荷较低，脓毒症后存活率提高，这表明eCIRP 有害作用可能是由于受损的细菌清除。事实上，eCIRP显著降低了 巨噬细胞吞噬E.通过细胞骨架麻痹。eCIRP还诱导了巨噬细胞的形成， 噬菌体细胞外陷阱和细胞外陷阱降低了死亡细胞的巨噬细胞吞噬作用。我们有 鉴定了髓样细胞-1（TREM-1）上表达的触发受体是eCIRP受体，并且 TREM-1活化在eCIRP介导的巨噬细胞吞噬功能障碍中起关键作用。此外，委员会认为， 在TREM-1-/-小鼠中，TBI后30天的存活率显著提高。基于这些新发现，我们 假设电离辐射后释放eCIRP激活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，新的抑制剂 M3减少了eCIRP与TREM-1的结合，并改善了脓毒症后的存活率。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吞噬功能，从而 改善单独遭受辐射损伤或并发脓毒症的小鼠的存活。本课题 计划进一步确定eCIRP对辐射诱导的巨噬细胞吞噬功能障碍的关键作用， 确定eCIRP引起巨噬细胞吞噬功能障碍的机制，并将M3发展为 靶向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性免疫的发病机制提供新的机制见解， 功能障碍，以及一个新的医疗对策，为受害者的主要辐射暴露，或没有 败血症