Role of RBC-TLR9 in Acute Inflammatory Anemia

RBC-TLR9 在急性炎症性贫血中的作用

• 批准号: 10618182
• 负责人: Nilam S. Mangalmurti
• 金额: $ 20.31万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-05 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618182
• 关键词: Acceleration; Acute; Adoptive Transfer; Affect; Anemia; Anemia due to Chronic Disorder; Automobile Driving; Bacteremia; Bacterial DNA; Binding; Biological Assay; CD47 gene; Cell Aging; Cell physiology; Cell surface; Cells; Circulation; Clustered Regularly Interspaced Short Palindromic Repeats; Communicable Diseases; Critical Illness; Cytolysis; DNA; DNA Binding; DNA delivery; Data; Developing Countries; Development; Disease; Eating; Endosomes; Erythrocyte Transfusion; Erythrocytes; Erythroid; Erythroid Progenitor Cells; Erythrophagocytosis; Goals; Human; Immunologics; In Vitro; Infection; Inflammation; Inflammatory; Injury; Innate Immune Response; Knockout Mice; Knowledge; Laboratories; Life; Macrophage; Malaria; Mitochondrial DNA; Modeling; Morbidity - disease rate; Morphology; Mus; Nature; Nucleic Acid Binding; Nucleic Acids; Osmotic Fragility test; Outcome; Oxygen; Parasites; Parasitic infection; Pathogenesis; Patients; Phagocytes; Plasmodium; Play; Population; Prevalence; Process; Production; Role; Sepsis; Severities; Signal Transduction; Sterility; System; TLR9 gene; Testing; Toddler; Transfusion; Viral; antagonist; circulating DNA; immune activation; in vivo; in vivo Model; in vivo evaluation; inflammatory modulation; insight; malarial anemia; mortality; mouse model; new therapeutic target; novel therapeutics; organ injury; preservation; prevent; senescence; stem cells

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.

项目摘要/摘要：贫血的全球负担很高，全球患病率为25％。贫血 是传染病的标志，包括寄生虫感染，并且在发展中国家经常致命， 威胁生命的疟疾贫血影响婴儿和幼儿。在世界其他地区，贫血 在重症患者中非常普遍，几乎所有患者在ICU住院期间患有贫血。在这个 人口，RBC输血与发病率和死亡率的增加有关。机械 考虑到高度，迫切需要了解对感染和危害疾病的急性贫血的理解 发病率，死亡率以及一定人群中输血的潜在危害。一个基本和关键的 知识差距缺乏对红细胞（RBC）如何促进先天免疫的理解 反应和炎症性贫血。 RBC是被动旁观者还是积极贡献 急性炎症性贫血的发展尚不清楚。 DNA感应是先天的重要组成部分 对感染和无菌损伤的免疫反应，以及吞噬细胞中的核酸传感-TLR与 发生炎症性贫血，在细菌败血症和寄生虫感染中经常观察到。 我们最近发现，RBC表达核酸受体TLR9和无CPG结合的核酸受体 脱氧核糖核酸。在炎症状态下，RBCS从循环中捕获DNA并经历形态学变化 并加速衰老。我们的初步数据表明，RBC，而不是吞噬细胞，TLR9驱动 加速红细胞增多。因为升高的无细胞CpG-DNA和急性贫血是常见的特征 败血症，寄生虫感染和无菌炎症，我们假设RBC-TLR9捕获核酸 因此，红细胞增多症代表了急性炎症性贫血的普遍机制。基于 通过这一假设，我们将使用人类红细胞衍生的祖细胞来解决两个目标，从遗传上讲 不足的小鼠和寄生虫感染，败血症，贫血和无菌炎症的体内模型。在AIM 1中，我们 将确定CPG诱导的RBC衰老是否取决于RBC-TLR9。在AIM 2中，我们将评估 TLR9在体内驱动炎症性贫血中的红细胞特异性作用。我们将询问RBC-DNA结合是否足够 引起贫血以及RBC清除是否取决于红细胞TLR9。我们还将确定 RBC-TLR9在感染和无菌炎症期间贫血发展中的谱系特异性功能 结合了遗传缺陷的小鼠和RBC转移模型。虽然本质上探索性 通过红细胞发现通用的核酸敏感机制，可能会阐明 炎症性贫血和提议的目标的完成可能会为此提供新的治疗剂的见解 高度普遍的疾病。