Macrophage Metabolism and Inflammation in Metabolic Disease

代谢性疾病中的巨噬细胞代谢和炎症

基本信息

批准号：
9920593
负责人：
Joel David Schilling
金额：
$ 34.31万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2021-12-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920593
关键词：
ASCL1 gene Acyl Coenzyme A Address Affect Amputation Attenuated Biological Assay Biology Cell physiology Cells Cleaved cell Clinical Complex Complications of Diabetes Mellitus Coupled Defect Diabetes Mellitus Diabetic mouse Disease Enzymes Family member Fatty Acids Functional disorder Genetic Genetic Models Goals Health Impaired wound healing Impairment In Vitro Inflammasome Inflammation Inflammatory Innate Immune System Interleukin-1 beta Investigation Knock-out Knowledge Link Lipids Literature Lysosomes Mediator of activation protein Metabolic Metabolic Diseases Metabolism Mission Mitochondria Modeling Molecular Molecular Target Mus Myeloid Cells Nuclear Receptors Nutrient PPAR gamma Pathway interactions Pharmacology Play Process Production Public Health Research Role Site Skin injury Skin wound healing Small Interfering RNA Stress Testing Therapeutic Tissues United States National Institutes of Health Work base cell type cytokine diabetic diabetic ulcer diabetic wound healing disability fatty acid metabolism fatty acid oxidation genetic approach healing improved improved outcome in vivo inhibitor/antagonist injured insight lipid metabolism macrophage metabolic phenotype metabolomics novel novel therapeutic intervention oxidation programs response tissue repair tool transcription factor wound healing

项目摘要

ABSTRACT Dysfunctional inflammatory and wound healing responses are clinically important complications of diabetes, however the mechanisms underlying these defects remain elusive. Macrophages are cells of the innate immune system that orchestrate inflammatory and reparative responses. Evidence is emerging that macrophage dysfunction in diabetes contributes to inflammatory complications of this disease, including poor healing of skin wounds. While the mechanisms of macrophage dysfunction in diabetes are not well understood, it has recently become apparent that excess release of the cytokine IL- 1β promotes adverse wound healing. IL-1β release is regulated by the inflammasome, a pro- inflammatory complex that cleaves and activates IL-1β. In diabetes, elevated levels of circulating lipids promote macrophage lysosome damage and inflammasome activation; yet, the mechanistic links between macrophage lipid handling and IL-1β release are unclear. At sites of inflammation, macrophages undergo a shift in cellular metabolism towards fatty acid and mitochondrial oxidation pathways, a process regulated in part by the nuclear receptor transcription factor PPARγ. We hypothesize that when this metabolic shift occurs in the setting of excess lipid, macrophage lysosome damage and inflammasome activation will be enhanced. The main objective of this proposal is to determine how macrophage fatty acid metabolism contributes to inflammasome activation and poor wound healing in diabetics and to leverage this knowledge for translational investigation. Our preliminary studies demonstrate that PPARγ deficient macrophages have reduced rates of mitochondrial fatty acid utilization and less IL-1β release in response to lipid-inflammatory stress. In Aim 1, the mechanistic link between nutrient excess, mitochondrial lipid handling, and inflammasome activation will be dissected in primary macrophages in vitro. Genetic and pharmacologic approaches in combination with metabolic phenotyping, metabolomics analyses, and cell function assays will be employed. Aim 2 will then assess diabetic skin wound healing in two genetic models of macrophage fatty acid oxidation deficiency to address the in vivo links between macrophage lipid stress, inflammasome activation, and poor wound healing. In Aim 3, the effects of pharmacologic modulators of lipid metabolism on diabetic wound healing and inflammasome activation will be investigated. The results of these studies will be an important first step in the long-term goal of this research program, which is to dissect the mechanisms by which nutrient stress can impair macrophage inflammatory and reparative function in metabolic disease. The proposed studies aim to elucidate novel molecular targets that alter the crosstalk between fatty acids, mitochondrial oxidation and the inflammasome. This work is likely to have a strong positive impact on the field through identification of new pathways relevant to the treatment of diabetic wound healing complications.

抽象的功能失调的炎症和伤口愈合反应是临床上重要的并发症糖尿病，但是这些缺陷的基础机制仍然难以捉摸。巨噬细胞是安排炎症和修复反应的先天免疫系统。证据是糖尿病中的巨噬细胞功能障碍有助于这种炎症并发症疾病，包括皮肤伤口治愈不佳。而巨噬细胞功能障碍的机制糖尿病尚不清楚，最近显而易见，超过细胞因子IL-的释放 1β促进不良伤口愈合。 IL-1β释放受炎性体的调节，一种裂解并激活IL-1β的炎性复合物。在糖尿病中，循环脂质水平升高促进巨噬细胞溶酶体损伤和炎症体激活；但是，机械链接巨噬细胞脂质处理和IL-1β释放之间尚不清楚。在炎症部位巨噬细胞经历细胞代谢向脂肪酸和线粒体氧化的转变途径，该过程部分由核接收器转录因子PPARγ调节。我们假设，当这种代谢转移发生在多余的脂质溶酶体的情况下损伤和炎症体激活将得到增强。该提议的主要目的是确定巨噬细胞脂肪酸代谢如何有助于炎症体激活和较差糖尿病患者的伤口愈合，并利用这些知识进行翻译研究。我们的初步研究表明，PPARγ缺乏的巨噬细胞降低了线粒体脂肪酸的速率响应脂质炎性应激的利用和IL-1β释放较少。在AIM 1中，机械链接在营养过量，线粒体脂质处理和炎性体激活之间将在体外原发性巨噬细胞。遗传和药物方法与代谢结合表型，代谢组学分析和细胞功能分析将被录用。 AIM 2然后评估巨噬细胞脂肪酸氧化缺乏的两个遗传模型中的糖尿病皮肤伤口愈合至解决巨噬细胞脂质应激，炎症体激活和伤口不良之间的体内联系康复。在AIM 3中，脂质代谢的药物调节剂对糖尿病伤口愈合的影响并将研究炎症体激活。这些研究的结果将是重要的第一踏入该研究计划的长期目标，即剖析营养的机制压力会损害代谢疾病中巨噬细胞的炎症和修复功能。提议研究旨在阐明改变脂肪酸之间串扰的新型分子靶标氧化和炎性体。这项工作可能会对该领域产生强烈的积极影响鉴定与治疗糖尿病伤口愈合并发症有关的新途径。