Regulation of splenic resident tissue macrophage development and iron metabolism

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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.