Adipose Macrophage Iron Handling

脂肪巨噬细胞铁处理

• 批准号: 10164771
• 负责人: Alyssa H Hasty
• 金额: $ 50.09万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164771
• 关键词: Adipocytes; Adipose tissue; Affect; Bioenergetics; Biogenesis; Bone Marrow; Cells; Contracts; DNA; DNA biosynthesis; Data; Dependence; Disease; Dose; Environment; Epidemic; Erythrocytes; Erythropoiesis; Exposure to; Fasting; Ferritin; Free Radicals; Gene Expression; Genes; Glucose; Glucose Clamp; Haptoglobins; Health; Hemoglobin; Homeostasis; Impairment; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Innate Immune System; Insulin; Iron; Iron Isotopes; Iron Overload; Iron-Dextran Complex; Kupffer Cells; Laboratories; Lead; Lipids; Liposomes; Literature; Metabolic; Mitochondria; Mus; Nutrient; Obesity; Pathway interactions; Phenotype; Physiological; Prevention; Production; Property; Proteins; Publications; Recycling; Respiration; Risk; Role; Serum; Signal Transduction; TFRC gene; Thinness; Tissue Expansion; Tissues; Work; adipocyte differentiation; arm; base; blood glucose regulation; cell type; diet-induced obesity; environmental enrichment for laboratory animals; hemoglobin-haptoglobin receptor; holotransferrin; insulin sensitivity; iron metabolism; lipid biosynthesis; macrophage; metabolomics; metal transporting protein 1; oxidative damage; receptor; senescence; tissue repair; transcriptome sequencing

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.

铁动员的系统控制具有两个主要功能：为红细胞生成提供铁， 在抑菌期间消耗铁。然而，身体中的每个细胞都需要铁-用于呼吸，DNA合成， 增殖;而铁过载可导致蛋白质、DNA和脂质的氧化损伤。因此，铁 在组织和细胞水平的浓度必须由互补的机制精确地控制， 和微调系统控制。网状内皮细胞明显适合于从衰老细胞中回收铁， 红细胞通过其高表达的CD 163，血红蛋白/触珠蛋白受体，这是唯一的 表达于M2样M β上。我们的过度假设是，组织巨噬细胞（M β）是“铁稳态”， 感知和响应局部组织的铁需求。巨噬细胞的这种作用在脂肪组织中尤为重要 (AT);在该组织中脂肪生成需要足够的水平，其必须更迅速地扩张和收缩 比任何其他组织，防止自由基的产生是特别重要的，在一个脂质丰富的 环境 巨噬细胞不仅仅是先天免疫系统的细胞，它们是抵抗感染的关键防御者。事实上， 它们存在于所有组织中，并根据其局部环境显示出显著的可塑性。这种可塑性 需要在从M1样炎性组织到M2样组织的表型谱上快速极化 修复表型我们已经确定了一个独特的亚群的ATM细胞，有一个铁循环表型 并且是高度M2极化的1。此外，我们表明，这些专门的M β细胞吸收多余的铁， 保护脂肪细胞免受铁超载2.我们把这些铁制的自动取款机称为MFehi， 自动取款机的名字是MFelo。MFehi M β表达高水平的铁相关基因，如CD 163、转铁蛋白受体 （TfR 1）和铁输出蛋白ferroportin（Fpn）。虽然我们的MFehi细胞表达一些M2基因， 有趣的初步数据显示，MFehi生物能量学不同于M2生物能量学，这表明 AT MFehi细胞是唯一极化的。根据我们的数据，我们假设：适当的铁处理 创造了一种独特的极化ATM细胞表型，增强了它们影响脂肪形成的能力， AT中胰岛素的作用。在我们的三个目标中，我们将确定以下方面的程度： 影响极化和内在免疫代谢，2）ATM铁处理影响脂肪细胞 分化、胰岛素敏感性和AT扩张，3）失调的ATM细胞极化和铁处理 有助于AT健康和营养过剩期间的全身胰岛素作用。