Role of RBC-TLR9 in Acute Inflammatory Anemia

RBC-TLR9 在急性炎症性贫血中的作用

基本信息

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
项目类别：
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

项目摘要

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（包括寄生虫感染）的一个标志，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，贫血在重症患者中非常普遍，几乎所有患者在 ICU 住院期间都会出现贫血。在这个在人群中，红细胞输注与发病率和死亡率增加有关。机械论鉴于高感染率，迫切需要了解以感染和危重疾病为特征的急性贫血。特定人群的发病率和死亡率以及输血的潜在危害。一项基本且关键的知识差距是指对红细胞 (RBC) 如何促进先天免疫缺乏了解反应和炎症性贫血。红细胞是被动的旁观者还是积极的贡献者急性炎症性贫血的发生尚不清楚。 DNA 传感是先天感知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感应 TLR 与发生炎症性贫血，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TLR9并结合含有游离CpG的细胞脱氧核糖核酸。在炎症状态下，红细胞从循环中捕获 DNA 并发生形态变化并加速衰老。我们的初步数据表明 TLR9 驱动的是 RBC，而不是吞噬细胞加速红细胞吞噬作用。因为游离 CpG-DNA 升高和急性贫血是常见特征对于脓毒症、寄生虫感染和无菌性炎症，我们假设 RBC-TLR9 的核酸捕获随之而来的噬红细胞作用代表了急性炎症性贫血的普遍机制。基于根据这一假设，我们将使用人类红细胞衍生的祖细胞来解决两个目标有缺陷的小鼠，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 RBC 衰老是否依赖于 RBC-TLR9。在目标 2 中，我们将评估 TLR9 在驱动体内炎症性贫血中的红系特异性作用。我们会询问 RBC-DNA 结合是否足够引起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红细胞转移模型的组合。在本质上是探索性的，发现红细胞的通用核酸传感机制可能会阐明红细胞的关键决定因素炎症性贫血，完成拟议的目标可能会为该病的新疗法提供见解高度流行的疾病。