The Role of Erythroblastic Islands in Anemia of Inflammation

项目摘要/摘要 哺乳动物的终末红细胞生成发生在造红细胞岛(EBI)内，造红细胞岛是红细胞形成的壁龛 在与中央(哺乳)巨噬细胞的密切互动中区别对待。尽管EBI在1958年被描述为 马塞尔·贝西斯作为第一个造血利基，仍有许多问题需要回答，以提高我们的 了解它们的结构和功能。 炎症性贫血(AOI)发生在慢性或急性免疫激活的患者(由于感染性、 恶性疾病或自身免疫性疾病)，并影响全世界数百万人的生活质量。 本应用程序的总体目标是了解EBI作为红系造血剂的结构和功能 正常、基线红细胞生成的生态位，以及在导致贫血的情况下这一点是如何改变的 发炎。我们的初步数据显示，F4/80、VCAM1和CD169通过 EBI内的中央巨噬细胞。与之形成鲜明对比的是，CD11b在EBI上呈低水平或负值 巨噬细胞，而它大量存在于岛屿内的其他细胞中。EBI内的CD11b+细胞是 与中央巨噬细胞(Mφ)接触的粒细胞前体。此外，儿童骨髓中的EB病毒 分离后，AOI小鼠的CD11b+细胞及其中心巨噬细胞数量增加 密度梯度沉积的EBI中，黏附分子P-选择素的表达增加 这就吸引了中性粒细胞。 我们假设中央EBIMφ为红细胞和粒细胞的生成提供了一个利基环境。 通过细胞间相互作用的动态平衡(基线)造血，同时优先支持 应激状态下的红细胞生成。相反，在炎症条件下，细胞的变化 中心型EBIφS样P-选择素表达增强，偏重粒系而不是红系，导致 你好。在这里，我们建议(1)定义小鼠和人的中枢EBI巨噬细胞特性的谱 小鼠胎肝和胎脾作为生理和病理模型 应激红细胞生成，(2)确定EBIφS与粒细胞的结构和功能相互作用 在基线条件下，在EBI内共存的前体，以及(3)评估EBI M-φ、S和粒细胞前体抑制急性期血清白蛋白生成及P-选择素阻断是否改善急性期血清白蛋白血症 动物模型。 这些研究将扩大我们对EBI MφS和 它们在造血中的作用，并阐明了管理AOI患者的新的治疗目标和策略， 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患者的发病率 世界范围内的疾病。

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.