Mechanisms of Radiation-Induced Innate Immune Dysfunction and Its Countermeasures

项目描述：核电站事故、恐怖主义和地缘政治不稳定 有遭受大规模辐射照射的风险。由于中性粒细胞在辐射后显著下降，巨噬细胞 担负着清除大多数易位或入侵细菌的重要作用。然而，很少有研究 评估了辐射对分化的、未分割的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)是一种新的 可导致先天免疫功能障碍的介体。在我们的初步研究中，我们已经显示出 体内、外照射后eCIRP释放增加。CIRP中的不足改善了 全身照射(TBI)小鼠的存活情况。脓毒症显著恶化了脑外伤后的存活率， 但CIRP-/-小鼠在脓毒症后细菌载量较低，存活率提高，这表明eCIRP 有害的影响可能是由于细菌清除受损所致。事实上，eCIRP显著减少了 巨噬细胞通过细胞骨架麻痹吞噬大肠杆菌。ECIRP还诱导了宏观的形成。 噬菌体胞外陷阱和胞外陷阱减少了死亡细胞的巨噬细胞吞噬功能。我们有 证实髓系细胞上表达的触发受体-1(TREM-1)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。此外， 在TREM-1-/-小鼠中，TBI后30天的存活期显著提高。基于这些新发现，我们 假设电离辐射后释放的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，提高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的相互作用可以恢复巨噬细胞的吞噬功能，从而 提高单纯受到辐射损伤或并发脓毒症的小鼠的存活率。在这个项目中，我们 计划进一步确定eCIRP在辐射诱导的巨噬细胞吞噬功能障碍中的关键作用， 确定eCIRP导致巨噬细胞吞噬功能障碍的机制，并将M3发展为 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，以及对有或没有重大辐射暴露受害者的新医学对策 败血症。

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.