Adipose Macrophage Iron Handling

脂肪巨噬细胞铁处理

• 批准号: 10181590
• 负责人: Alyssa H Hasty
• 金额: $ 25.34万
• 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/10181590
• 关键词: Adipocytes; Adipose tissue; Affect; Bioenergetics; Biogenesis; Bone Marrow; Cells; Contracts; DNA; DNA biosynthesis; Data; Dependence; Diet; 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; 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.

铁动员的全身控制具有两个主要功能：为红细胞生成的铁和 在细菌杀菌期间耗尽铁。然而，体内每个细胞都需要铁 - 用于呼吸，DNA合成和 增殖;虽然铁超载会导致氧化物对蛋白质，DNA和脂质的损害。那是铁 在组织和细胞水平上的浓度必须由补充的机制准确控制 和微调系统控制。网状内皮m教明显适合从senscent中回收fe 红细胞通过其高表达CD163（血红蛋白/触觉受体）的高表达，它是独特的 在M2状的M ϕ上表达。我们的整理假设是组织巨噬细胞（M ϕ）是“费罗尔施塔者”， 感知和响应局部组织铁的需求。 M ϕs的这种作用在脂肪组织中尤其重要 （在）;在该组织中需要足够的水平才能更快地扩展和收缩 比任何其他组织，预防自由基产生在富含脂质的富含 环境。 M ϕ不仅仅是先天免疫系统的细胞，它们是针对感染的关键捍卫者。实际上， 它们驻留在所有组织中，并根据当地环境显示出显着的可塑性。这种可塑性 需要在从M1样炎症到M2样组织的表型上快速极化 修复表型。我们已经确定了具有铁回收表型的ATM ϕ的独特亚群 并且是高度M2极化1。此外，我们表明这些专业的M ϕ占据了多余的铁， 保护脂肪细胞免受铁超载2。我们将这些铁循环的ATM ϕ称为Mfehi，其余 AMT ϕ作为MFELO。 MFEHI M ϕ表达高水平的铁相关基因，例如CD163，转铁蛋白受体 （TFR1）和铁出口国铁蛋白（FPN）。虽然我们的MFEHI细胞表达了一些M2基因，但我们有 有趣的初步数据，表明Mfehi生物能学与M2生物能学不同，这表明 在Mfehi细胞上是独特的极化。以我们的数据为前提，我们假设：适当的铁处理 创建一个独特的极化ATMϕ表型，以增强其影响脂肪形成的能力 和胰岛素作用。在我们的三个目标中，我们将确定：1）Mϕ铁处理的程度 影响极化和内在免疫代谢，2）ATM ϕ铁处理影响脂肪细胞 分化，胰岛素灵敏度和扩展时，3）ATM ϕ极化和铁处理失调 在营养过剩过程中为健康和全身胰岛素作用做出贡献。