Adipose Macrophage Iron Handling

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Systemic control of iron mobilization serves two main functions: to provide iron for erythropoiesis and to deplete iron during bacteriostasis. Yet, every cell in the body requires iron – for respiration, DNA synthesis, and proliferation; while iron-overload can lead to oxidative damage to proteins, DNA, and lipid. Thus, iron concentrations at the tissue and cellular level must be exquisitely controlled by mechanisms that compliment and fine-tune systemic control. Reticuloendothelial Mϕs are distinctly suited to recycle Fe from senescent erythrocytes by their high expression of CD163, the hemoglobin/haptoglobin receptor, which is uniquely expressed on M2-like Mϕs. Our over-arching hypothesis is that tissue macrophages (Mϕs) are “ferrostats”, sensing and responding to local tissue iron needs. This role of Mϕs is particularly important in adipose tissue (AT); sufficient levels are required for adipogenesis in this tissue that must expand and contract more rapidly than any other tissue, and prevention of free radical production is particularly important in a lipid-enriched environment. Mϕs are not simply cells of the innate immune system that are critical defenders against infection. In fact, they reside in all tissues and show remarkable plasticity based upon their local environment. This plasticity requires rapid polarization on a spectrum of phenotypes ranging from M1-like inflammatory to M2-like tissue repair phenotypes. We have identified a unique subpopulation of ATMϕs that have an iron-recycling phenotype and are highly M2-polarized1. Furthermore, we show that these specialized Mϕs take up excess iron, protecting the adipocytes from iron overload2. We refer to these iron cycling ATMϕs as MFehi and the remaining ATMϕs as MFelo. MFehi Mϕs express high levels of iron-related genes such as CD163, transferrin receptor (TfR1), and the iron exporter, ferroportin (Fpn). While our MFehi cells express some M2 genes, we have intriguing preliminary data showing that MFehi bioenergetics are different than M2 bioenergetics, suggesting that AT MFehi cells are uniquely polarized. Premised on our data, we hypothesize that: proper iron handling creates a uniquely polarized ATMϕ phenotype that enhances their ability to influence adipogenesis and insulin action in AT. In our three aims, we will determine the extent to which: 1) Mϕ iron processing influences polarization and intrinsic immunometabolism, 2) ATMϕ iron handling impacts adipocyte differentiation, insulin sensitivity and AT expansion, 3) Dysregulated ATMϕ polarization and iron handling contribute to AT health and systemic insulin action during nutrient excess.