Regulation of splenic resident tissue macrophage development and iron metabolism

脾由驻留的和暂时招募的吞噬红细胞组成，这些细胞在控制和调节红细胞寿命和铁翻转方面起着关键作用。然而，这些离散细胞亚群的细胞起源和谱系多样性仍然不完全清楚。越来越多的证据表明，红髓驻留巨噬细胞(RPM)来自胚胎前体细胞，而适应代谢变化或贫血应激的瞬时细胞群则来自传统的骨髓来源的单核细胞。我们对各种条件性Notch信号缺陷小鼠的初步分析显示，驻留巨噬细胞存在缺陷，同时脾中有铁超载的证据，而基本红细胞参数在基线条件下没有变化。与此同时，突变小鼠表现出异常的单核细胞样群，表达部分吞噬红细胞的特征。在这项研究中，我们将研究Notch信号在出生前和出生后驻留巨噬细胞和瞬时吞噬红细胞的发育中的作用，并阐述在基线和贫血模型中，Notch信号在红细胞清除和铁代谢中的作用。我们将具体解决以下问题：1)Notch信号如何调节脾内滞留巨噬细胞的发育；2)脾巨噬细胞/红细胞的发育来源和细胞组成；3)Notch调节的巨噬细胞在铁代谢和代谢和细胞对贫血的适应中所起的作用。这将阐明胚胎巨噬细胞发育中的谱系承诺和功能的调节，这是一个重要但知之甚少的话题。

The spleen consists of resident and transiently recruited erythrophagocytic cell populations critically involved in control and regulation of erythrocyte life-span and iron turn-over. However, the cellular origin and lineage diversity of these discrete cell subsets are still incompletely understood. There is emerging evidence that red pulp resident macrophages (RPM) are derived from embryonic precursors, while transient cell populations arising in adaptation to metabolic changes or anemic stress are derived from conventional bone-marrow derived monocytes. Our preliminary analysis in various conditional Notch signaling-deficient mice shows defects in resident macrophages, along with evidence of iron overload, in the spleen, while basic erythrocyte parameters are unchanged under baseline conditions. At the same time, mutant mice show aberrant monocyte-like populations expressing a partially erythrophagocytic profile. In this proposal, we will study the role of Notch signaling in the development of resident macrophages and transient erythrophagocytic cells in the pre- and postnatal period and address the functional role in erythrocyte removal and iron metabolism, both at baseline and in an anemia model. We will specifically address the following questions: 1) How does Notch signaling regulate splenic resident macrophage development; 2) What is the developmental origin and the cellular composition of splenic macrophages/erythrophagocytes; 3) What is the role of Notch-regulated macrophages in iron metabolism and the metabolic and cellular adaptation to anemia. This will clarify regulation of lineage commitment and function in embryonic macrophage development, an important but poorly understood topic.