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: 10352593
• 负责人: Nilam S. Mangalmurti
• 金额: $ 24.38万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352593
• 关键词: Acute; Address; Adoptive Transfer; Affect; Anemia; Anemia due to Chronic Disorder; Automobile Driving; Bacteremia; Bacterial DNA; Binding; Biological Assay; Blood Circulation; CD47 gene; Cell Aging; Cell physiology; Cell surface; Cells; 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; Malaria; Masks; 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; base; circulating DNA; immune activation; in vivo; in vivo Model; in vivo evaluation; insight; macrophage; 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：全球贫血负担高，全球患病率为25%。贫血