Regulation of splenic resident tissue macrophage development and iron metabolism

脾脏由常驻和短暂募集的吞噬红细胞群组成，这些细胞群关键性地参与红细胞寿命和铁周转的控制和调节。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。有新的证据表明，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产生的瞬时细胞群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，脾脏中常驻巨噬细胞存在缺陷，沿着铁过载的证据，而基础红细胞参数在基线条件下未发生变化。与此同时，突变小鼠显示异常的单核细胞样群体表达部分吞噬红细胞的概况。在这项提案中，我们将研究Notch信号在出生前和出生后时期的常驻巨噬细胞和瞬时红细胞吞噬细胞的发育中的作用，并在基线和贫血模型中解决红细胞去除和铁代谢中的功能作用。我们将具体解决以下问题：1）Notch信号如何调节脾脏驻留巨噬细胞的发育; 2）脾脏巨噬细胞/红细胞的发育起源和细胞组成是什么; 3）Notch调节的巨噬细胞在铁代谢和代谢中的作用以及对贫血的细胞适应。这将阐明胚胎巨噬细胞发育中谱系定型和功能的调节，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.