The Role of Erythroblastic Islands in Anemia of Inflammation

成红细胞岛在炎症性贫血中的作用

• 批准号: 10377395
• 负责人: Lionel Blanc
• 金额: $ 61.99万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377395
• 关键词: Acute; Adhesives; Adult; Affect; Anemia; Anemia due to Chronic Disorder; Animal Model; Autoimmune Diseases; Biological Assay; Bone Marrow; Cell Nucleus; Cells; Cellular Structures; Characteristics; Chronic; Communicable Diseases; Complication; Coupled; DNA; Data; Defect; Discipline of Nursing; Disease; Dysmyelopoietic Syndromes; Erythroblasts; Erythrocytes; Erythroid; Erythropoiesis; Fetal Liver; Fetal Spleen; Flow Cytometry; Fostering; Genes; Genetic; Goals; Granulopoiesis; Growth Factor; Hematology; Hematopoiesis; Hematopoietic; Hemoglobin; Heterogeneity; Homeostasis; Human; ITGAM gene; Image; In Situ; In Vitro; Inflammation; Inflammatory; Iron; Island; Knockout Mice; Knowledge; Label; Malignant - descriptor; Mammals; Mediator of activation protein; Methods; Microscopy; Modeling; Morbidity - disease rate; Mus; P-Selectin; Pathologic; Patients; Persons; Pharmacology; Phenotype; Population; Population Heterogeneity; Process; Production; Quality of life; Recovery; Reporting; Role; Sedimentation process; Stress; Structure; Surface; TFRC gene; Testing; Thalassemia; Therapeutic Intervention; Toxic effect; base; density; differential expression; follow-up; granulocyte; hematopoietic tissue; immune activation; improved; in vivo; insight; macrophage; mortality; mouse model; neutrophil; new therapeutic target; novel; physiologic model; prevent; reconstitution; single-cell RNA sequencing

Project Summary/Abstract Terminal erythropoiesis in mammals occurs within the erythroblastic islands (EBIs), niches where erythroblasts differentiate in close interaction with a central (nursing) macrophage. Although EBIs were described in 1958 by Marcel Bessis as the first hematopoietic niche, there are still many questions to be answered to improve our understanding of their structure and function. Anemia of inflammation (AoI) occurs in patients with chronic or acute immune activation (due to an infectious, malignant, or autoimmune disease) and affects the quality of life of millions of people worldwide. The overall goal of this application is to understand the structure and function of the EBI as the erythropoietic niche in normal, baseline erythropoiesis and how this is modified in conditions leading to anemia of inflammation. Our preliminary data show that F4/80, VCAM1, and CD169 are expressed heterogeneously by the central macrophages within the EBIs. In marked contrast, CD11b is low or negative on the EBI macrophage, while it is abundantly present on other cells within the islands. The CD11b+ cells within EBIs are granulocyte precursors in contact to the central macrophage (Mφ). Moreover, EBIs in the bone marrow of mice with AoI have increased number of CD11b+ cells and their central macrophages, evaluated after isolation of EBIs with gradient density sedimentation, have increased expression of P-selectin, an adhesive molecule that attracts neutrophils. We hypothesize that the central EBI Mφ provides a niche for both erythropoiesis and granulopoiesis at homeostatic (baseline) hematopoiesis through intercellular interactions, while it preferentially supports erythropoiesis in stress erythropoiesis conditions. In contrast, under conditions of inflammation, changes of the central EBI Mφs like increased P-selectin expression, favor granulopoiesis versus erythropoiesis, leading to AoI. Here, we propose to (1) define the spectrum of the central EBI macrophage identity in mouse and human BM at baseline conditions, and in mouse fetal liver and spleen as models of physiological and pathological stress erythropoiesis, (2) determine structural and functional interactions of the EBI Mφs with the granulocyte precursors co-existing within EBIs at baseline conditions, and (3) evaluate the mechanisms by which the EBI Mφs and granulocyte precursors in AoI suppress erythropoiesis and test if P-selectin blockage improves AoI in animal models. These studies will expand our knowledge on the fundamental questions regarding the identity of EBI Mφs and their role in hematopoiesis and illuminate novel therapeutic targets and strategies to manage patients with AoI, a common complication increasing morbidity in millions of patients with malignant, infectious, or autoimmune diseases, worldwide.

项目总结/摘要 哺乳动物中的终末红细胞生成发生在成红细胞岛（EBI）内， 与中央（护理）巨噬细胞密切相互作用而分化。虽然EBI在1958年就被描述为 作为第一个造血利基，仍然有许多问题需要回答，以提高我们的 了解其结构和功能。 炎症性贫血（AoI）发生在慢性或急性免疫激活（由于感染性， 恶性或自身免疫性疾病）并影响全世界数百万人的生活质量。 本申请的总体目标是了解EBI作为红细胞生成因子的结构和功能。 在正常，基线红细胞生成中的小生境，以及在导致贫血的条件下这是如何改变的。 炎症我们的初步数据显示，F4/80、VCAM 1和CD 169在细胞中的表达是不均一的。 EBI中的中央巨噬细胞。与此形成鲜明对比的是，CD11b在EBI上是低的或阴性的 巨噬细胞，而它是大量存在于其他细胞内的岛屿。EBI中的CD11b+细胞是 与中央巨噬细胞（M φ）接触的粒细胞前体。此外，骨髓中的EBI 分离后评估，患有AoI的小鼠的CD11b+细胞及其中央巨噬细胞的数量增加 EBI的梯度密度沉降，增加了P-选择素的表达， 吸引中性粒细胞 我们推测，中央EBI M φ为红细胞生成和粒细胞生成提供了一个小生境， 稳态（基线）造血通过细胞间的相互作用，而它优先支持 在应激红细胞生成条件下的红细胞生成。相反，在炎症条件下， 中央EBI M φ样P-选择素表达增加，有利于粒细胞生成而不是红细胞生成，导致 AoI。在这里，我们建议（1）定义小鼠和人的中央EBI巨噬细胞特性的谱 在基线条件下的BM，以及在小鼠胎肝和脾中作为生理和病理模型， 应激红细胞生成，（2）确定EBI M φ与粒细胞的结构和功能相互作用 在基线条件下EBI内共存的前体，以及（3）评估EBI AoI中的M φ和粒细胞前体抑制红细胞生成，并测试P-选择素阻断是否改善AoI。 动物模型 这些研究将扩大我们对有关EBI M φ身份的基本问题的认识， 它们在造血中的作用，并阐明了新的治疗靶点和策略来管理患有AoI的患者， 一种常见的并发症，增加了数百万恶性、感染性或自身免疫性疾病患者的发病率。 疾病，全世界。