Adipose Macrophage Iron Handling

脂肪巨噬细胞铁处理

• 批准号: 10415905
• 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/10415905
• 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.

铁动员的系统控制有两个主要功能：为红细胞生成提供铁和 在抑菌过程中消耗铁。然而，体内的每个细胞都需要铁——用于呼吸、DNA 合成和 增殖;而铁过量会导致蛋白质、DNA 和脂质氧化损伤。因此，铁 组织和细胞水平的浓度必须通过补充的机制精确控制 并微调系统控制。网状内皮 Mphis 非常适合从衰老中回收 Fe 红细胞通过高表达 CD163（血红蛋白/触珠蛋白受体）而发挥作用，这是独一无二的 用类似 M2 的 Mphis 表示。我们的首要假设是组织巨噬细胞 (Mphis) 是“ferrostats”， 感知并响应局部组织的铁需求。 Mphis 的这种作用在脂肪组织中尤其重要 （在）;该组织中的脂肪生成需要足够的水平，必须更快地扩张和收缩 比任何其他组织，预防自由基的产生对于富含脂质的组织尤为重要 环境。 Mphis 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。实际上， 它们存在于所有组织中，并根据当地环境表现出显着的可塑性。这种可塑性 需要对从 M1 样炎症组织到 M2 样组织的一系列表型进行快速极化 修复表型。我们已经确定了具有铁回收表型的 ATMphis 的独特亚群 并且高度 M2 极化1。此外，我们表明这些专门的 Mphi 吸收了多余的铁， 保护脂肪细胞免受铁过载的影响2。我们将这些铁循环 ATM 称为 MFehi，其余的 ATMphis 为 MFelo。 MFehi Mphis 表达高水平的铁相关基因，例如 CD163、转铁蛋白受体 (TfR1) 和铁输出蛋白铁转运蛋白 (Fpn)。虽然我们的 MFehi 细胞表达一些 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 AT MFehi 细胞具有独特的极化。根据我们的数据，我们假设： 正确的铁处理 创建独特的极化 ATMphi 表型，增强其影响脂肪生成的能力 和 AT 中胰岛素的作用。在我们的三个目标中，我们将确定以下程度： 1) Mφ 铁加工 影响极化和内在免疫代谢，2) ATMφ 铁处理影响脂肪细胞 分化、胰岛素敏感性和 AT 扩张，3) ATM 极化和铁处理失调 在营养过剩期间有助于 AT 健康和全身胰岛素作用。