Adipose Macrophage Iron Handling

脂肪巨噬细胞铁处理

基本信息

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
项目类别：
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

项目摘要

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.

铁动员的全身控制有两个主要功能：为红细胞生成提供铁和然而，体内的每个细胞都需要铁来进行呼吸、DNA 合成和生长。增殖；而铁超载会导致蛋白质、DNA 和脂质氧化损伤。组织和细胞水平的浓度必须通过补充的机制精确控制和微调系统控制，网状内皮细胞 Mphis 非常适合从衰老中回收铁。红细胞通过高表达 CD163（血红蛋白/触珠蛋白受体）而发挥作用，这是独一无二的我们的总体假设是组织巨噬细胞 (Mphis) 是“ferrostats”， Mψs 的这种作用在脂肪组织中尤其重要。 (AT)；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。 Mphi 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。它们存在于所有组织中，并根据其局部环境表现出显着的可塑性。需要对从 M1 样炎症到 M2 样组织的一系列表型进行快速极化我们已经鉴定出具有铁回收表型的独特 ATM 亚群。并且是高度 M2 极化的1 此外，我们表明这些特殊的 Mψ 会吸收多余的铁，保护脂肪细胞免受铁过载2 我们将这些铁循环 ATM 称为 MFehi ，其余的称为 MFehi 。 ATMφs 为 MFelo。MFehi Mφs 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性，以我们的数据为前提，我们发现：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胰岛素在 AT 中的作用在我们的三个目标中，我们将确定以下程度： 1) Mφ 铁处理。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。