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/总结：贫血的全球负担很高，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，在发展中国家往往是致命的， 危及生命的疟疾性贫血，主要影响婴儿和幼儿。在世界其他地方， 在重症患者中非常普遍，几乎所有患者在ICU住院期间都会发生贫血。在这 在人群中，RBC输注与发病率和死亡率增加相关。一种机械的 急性贫血的特点感染和危重病的理解是迫切需要考虑到高， 发病率和死亡率以及输血在特定人群中的潜在危害。一个基本的和关键的 知识差距是缺乏对红细胞（RBC）如何促进先天免疫的理解 反应和炎性贫血。红细胞是被动的旁观者还是积极参与 急性炎性贫血的发展是未知的。DNA感应是先天免疫系统的重要组成部分， 对感染和无菌损伤的免疫应答以及吞噬细胞中的核酸敏感TLR参与了 发生炎性贫血，这在细菌性败血症和寄生虫感染期间经常观察到。 我们最近发现，红细胞表达核酸受体TLR 9，并结合无细胞的含CpG的 DNA.在炎症状态下，红细胞从循环中捕获DNA并发生形态学变化 加速衰老我们的初步数据表明，红细胞，而不是吞噬细胞，TLR 9驱动 加速的红细胞吞噬作用。由于无细胞CpG-DNA升高和急性贫血是常见的特征， 败血症、寄生虫感染和无菌性炎症，我们假设RBC-TLR 9的核酸捕获 并且随后的红细胞吞噬作用代表了急性炎性贫血的普遍机制。基于 基于这一假设，我们将利用人红系衍生祖细胞， 缺陷型小鼠和寄生虫感染、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RBC衰老是否依赖于RBC-TLR 9。在目标2中，我们将评估 TLR 9在体内驱动炎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 导致贫血以及红细胞清除是否依赖于红细胞TLR 9。我们还将确定 RBC-TLR 9在感染和无菌性炎症期间贫血发展中的谱系特异性功能 使用遗传缺陷小鼠和RBC转移模型的组合。虽然是探索性质的， 发现红细胞的普遍核酸感应机制可能阐明 炎症性贫血，完成所提出的目标可能会提供深入了解新的治疗方法，这 高度流行的疾病。