Role of RBC-TLR9 in Acute Inflammatory Anemia

项目摘要/摘要：全球范围内的贫血症负担很重，全球患病率为25%。贫血 是包括寄生虫感染在内的传染病的标志，在发展中国家通常是致命的， 危及生命的疟疾贫血，主要影响婴儿和幼儿。在世界其他地区，贫血症 该病在危重病人中非常普遍，几乎所有患者在ICU期间都会患上贫血。在这 在人群中，红细胞输注与发病率和死亡率的增加有关。机械师 鉴于急性贫血的高发病率，迫切需要了解以感染和危重疾病为特征的急性贫血 在特定人群中输血的发病率、死亡率和潜在危害。一个基本而关键的问题 知识鸿沟是对红血球(RBC)如何促进先天免疫缺乏了解 反应和炎症性贫血。无论RBC是被动的旁观者还是积极地为 急性炎症性贫血的发展尚不清楚。DNA传感是人类与生俱来的 对感染和无菌损伤的免疫反应以及吞噬细胞中的核酸感应-TLRs参与了 出现炎症性贫血，常见于细菌败血症和寄生虫感染。 我们最近发现，红细胞表达核酸受体TLR9，并结合含有CpG的游离细胞 DNA在炎症状态下，红细胞从循环中捕获DNA并经历形态变化 加速衰老。我们的初步数据表明，驱动TLR9的是红细胞，而不是吞噬细胞 加速红细胞吞噬。因为游离CpG-DNA升高和急性贫血是常见的特征 对于脓毒症、寄生虫感染和无菌炎症，我们假设RBC-TLR9捕获核酸 随之而来的红细胞吞噬反应是急性炎症性贫血的普遍机制。基座 在这一假设的基础上，我们将利用人类红系祖细胞从基因上解决两个目的 缺陷小鼠，以及寄生虫感染、败血症、贫血和无菌炎症的体内模型。在目标1中，我们 将确定CpG诱导的红细胞衰老是否依赖于RBC-TLR9。在目标2中，我们将评估 TLR9在体内驱动炎性贫血中的红系特异性作用。我们会问RBC-DNA结合是否足够 导致贫血以及红细胞清除是否依赖于红细胞TLR9。我们还将确定 RBC-TLR9在感染性贫血和无菌炎症中的谱系特异性功能 使用基因缺陷小鼠和红细胞转移模型的组合。虽然本质上是探索性的， 发现一种通用的红细胞核酸感知机制可能会阐明 炎症性贫血和拟议目标的完成可能为治疗这一疾病的新疗法提供洞察力 高度流行的疾病。

Project Abstract/Summary: The global burden of anemia is high, with a worldwide prevalence of 25%. Anemia is a hallmark of infectious diseases, including parasite infection, and is often lethal in developing countries, with life-threatening malarial anemia affecting predominantly babies and toddlers. In other parts of the world, anemia is highly prevalent in critically ill patients, with almost all patients developing anemia during their ICU stay. In this population, RBC transfusions are associated with increased morbidity and mortality. A mechanistic understanding of the acute anemia characterizing infection and critical illness is urgently needed given the high morbidity and mortality and potential harm of transfusions in select populations. One fundamental and critical knowledge gap is a lack of understanding of how red blood cells (RBCs) contribute to the innate immune response and inflammatory anemia. Whether RBCs are passive bystanders or actively contribute to the development of acute inflammatory anemia is unknown. DNA-sensing is an essential component of the innate immune response to infection and sterile injury, and nucleic acid sensing-TLRs in phagocytes are implicated in developing inflammatory anemia, which is frequently observed during bacterial sepsis and parasitic infections. We have recently found that RBCs express the nucleic acid receptor TLR9 and bind cell-free CpG-containing DNA. During inflammatory states, RBCs capture DNA from the circulation and undergo morphologic changes and accelerated senescence. Our preliminary data demonstrate that RBC, not phagocyte, TLR9 drives accelerated erythrophagocytosis. Because elevated cell-free CpG-DNA and acute anemia are features common to sepsis, parasite infection, and sterile inflammation, we hypothesize that nucleic acid capture by RBC-TLR9 and consequent erythrophagocytosis represents a universal mechanism of acute inflammatory anemia. Based upon this hypothesis, we will address two aims using human erythroid-derived progenitor cells, genetically deficient mice, and in vivo models of parasite infection, sepsis, anemia, and sterile inflammation. In aim 1, we will determine if CpG-induced RBC senescence is dependent on RBC-TLR9. In aim 2, we will evaluate the erythroid-specific role of TLR9 in driving inflammatory anemia in vivo. We will ask if RBC-DNA binding is sufficient to cause anemia and whether RBC clearance is dependent on erythrocyte TLR9. We will also determine the lineage-specific functions of RBC-TLR9 in the development of anemia during infection and sterile inflammation using a combination of genetically deficient mice and RBC transfer models. While exploratory in nature, discovering a universal nucleic acid-sensing mechanism by red cells may elucidate critical determinants of inflammatory anemia, and completion of the proposed aims may provide insight into novel therapeutics for this highly prevalent disease.