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.

项目摘要/摘要 哺乳动物中的终末红细胞生成发生在红细胞岛（EBIS）中 与中央（护理）巨噬细胞密切相互作用。尽管1958年描述了EBIS 马塞尔·贝西斯（Marcel Bessis）是第一个造血生态位，仍然有很多问题要回答以改善我们的 了解它们的结构和功能。 炎症贫血（AOI）发生在慢性或急性免疫激活的患者中（由于感染性， 恶性或自身免疫性疾病），影响全球数百万人的生活质量。 该应用程序的总体目标是将EBI的结构和功能理解为红细胞生成 在正常的基线红细胞生成中的利基市场，以及如何在导致贫血的条件下修改这种情况 炎。我们的初步数据表明，F4/80，VCAM1和CD169通过 EBIS内的中央巨噬细胞。在明显的对比中，CD11b在EBI上是低或负的 巨噬细胞，虽然它绝对存在于岛上的其他细胞上。 EBIS中的CD11b+细胞是 与中央巨噬细胞接触的粒细胞前体（Mφ）。此外，ebis在骨髓中 AOI的小鼠的CD11b+细胞数量增加及其中心巨噬细胞，在分离后进行了评估 具有梯度密度沉积的EBIS的表达增加，P-选择素，粘合剂分子 吸引中性粒细胞。 我们假设中央EBIMφ为促红细胞生成和粒状植物提供了一个利基市场 通过相互作用的相互作用，稳态（基线）造血作用，而它优先支持 压力性红细胞生成条件下的红细胞生成。相反，在炎症条件下 中央EBImφ，例如p-选择蛋白表达增加，有利于颗粒状与红细胞生成的粒子，导致 aoi。在这里，我们建议（1）定义小鼠和人类中央EBI巨噬细胞的频谱 BM在基线条件下，小鼠胎儿肝脏和脾脏作为生理和病理模型 应力红细胞生成，（2）确定EBIMφS与粒细胞的结构和功能相互作用 前体在基线条件下EBIS共存，（3）评估EBI的机制 AOI中的MφS和粒细胞前体抑制红细胞生成，并测试P-选择素阻塞是否可以改善AOI 动物模型。 这些研究将扩大我们对EBIMφ身份的基本问题的了解和 它们在造血症中的作用，并阐明了管理AOI患者的新型治疗靶标和策略 常见的并发症增加了数百万个恶性，感染或自身免疫的患者的发病率 疾病，全球。