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 铁超载会导致蛋白质、DNA和脂质的氧化损伤。因此，铁 组织和细胞水平的浓度必须由相互补充的机制精确地控制 和微调的系统控制。网状内皮MϕS非常适合从衰老中回收铁 由于红细胞高表达CD163，这是一种独特的血红蛋白/结合珠蛋白受体 在类M2的MϕS上表达。我们的总体假设是组织巨噬细胞(MϕS)是“铁质”， 感知和响应局部组织铁的需求。MϕS的这一角色在脂肪组织中尤为重要 (At)；该组织的脂肪生成需要足够的水平，才能更快地膨胀和收缩 比任何其他组织都重要，而防止自由基的产生在富含脂质的 环境。 MϕS不仅仅是天然免疫系统中的细胞，它们是抵御感染的关键防御者。事实上, 它们存在于所有组织中，并根据所处的环境表现出非凡的可塑性。这种可塑性 需要从M1样炎性组织到M2样组织的一系列表型的快速极化 修复表型。我们已经确定了ϕS的一个独特的亚群，它具有铁循环表型 并且是高度M2极化的1。此外，我们还发现，这些专门的MϕS吸收了过量的铁， 保护脂肪细胞免受铁超载2。我们把这些铁骑ATM的ϕS称为MFehi，其余的称为MFehi ATMϕS饰演MFelo。MFeHI MϕS高水平表达CD163、转铁蛋白受体等铁相关基因 (TfR1)和铁出口蛋白铁蛋白(FPn)。虽然我们的MFehi细胞表达一些M2基因，但我们有 耐人寻味的初步数据显示，MFeHI生物能量学不同于M2生物能量学，这表明 AT MFehi细胞是独特的极化。根据我们的数据，我们假设：适当的铁处理 创造一种独特的极化atmϕ表型，增强其影响脂肪形成的能力 胰岛素在AT中的作用。在我们的三个目标中，我们将确定：1)Mϕ铁加工 影响极化和内源性免疫代谢2)ATMϕ铁处理对脂肪细胞的影响 分化、胰岛素敏感性与血管紧张素转换酶扩张；3)ϕ极化异常与铁的处理 有助于AT健康和营养过剩期间的全身胰岛素作用。