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Mitochondrial metabolism and macrophage function post MI

心肌梗死后线粒体代谢和巨噬细胞功能

基本信息

批准号：
10630833
负责人：
Rong Tian
金额：
$ 69.62万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630833
关键词：
Affect Anabolism Anti-Inflammatory Agents Behavior Biological Assay Bone Marrow Carbon Cardiac Cardiac health Cells ChIP-seq Complex Cues Energy Metabolism Epigenetic Process Generations Glycolysis Heart Heart Diseases Immunology Impairment Infarction Infiltration Inflammatory Inflammatory Response Interleukin-13 Interleukin-4 Lead Leukocytosis Ligands Link Lipopolysaccharides Macrophage Macrophage Activation Measures Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Molecular Mus Myelogenous Myeloid Cells Myocardial Infarction NADH NADP Natural Immunity Outcome Oxidation-Reduction Oxidative Phosphorylation Oxygen Consumption Pattern Pentosephosphate Pathway Phagocytosis Phase Phenotype Play Production Proliferating Proteins RNA Sequences Research Respiration Role Signal Transduction Site System Testing Time Toll-like receptors Transcriptional Regulation cytokine heart function histone methylation histone modification interest ischemic injury metabolomics mitochondrial metabolism mortality post intervention recruit therapeutic target tissue repair transcriptome treatment effect wound healing

项目摘要

Abstract Macrophages are key components of innate immunity system. It emerged recently that macrophages play critical roles in heart health and diseases. Following myocardial infarction (MI), macrophage is recruited in high number to the infarct site and acts as a key regulator in post-MI remodeling, generating proinflammatory signals early and reparative cues later. However, it is not well understood how macrophage function is regulated during the period of rapid change. Of interest, transcriptome analysis of macrophage in the infarct zone showed a time- dependent reprogramming of mitochondrial function during the first week post-MI when macrophage phenotype transitions from proinflammatory to reparative. This raises the question whether mitochondrial metabolism in macrophage is causally linked to the outcome of post-MI remodeling, and if so, what the underlying mechanisms are. Immunology research finds that macrophage activation is accompanied by global rewiring of the metabolic pathway. Proinflammatory macrophage, elicited by Toll-like receptor ligands lipopolysaccharide (LPS), shifts it energy metabolism from oxidative phosphorylation towards glycolysis. Such a metabolic switch is thought to favor rapid energy production and increased demand for biosynthesis, and fuel pentose phosphate pathway for NADPH generation, all lead to high levels of ROS and proinflammatory cytokines. On the other hand, the Th2 cytokines IL-4 and IL-13 induce alternative activation which promotes anti-inflammatory activity, wound healing and tissue repair, and presents the opposite metabolic pattern. Although the metabolic switch has been well described, questions remain whether differential metabolic activity (i.e., use of glycolysis versus mitochondrial respiration) is a coincidence, a consequence of changes in phenotype, or a direct driver of macrophage function. It is also unclear whether similar mechanisms apply to cardiac macrophages. To decipher the mechanistic role of mitochondrial function in macrophage phenotype, we analyzed the phenotype of macrophage with impaired mitochondrial respiration due to deletion of Ndufs4, a mitochondrial Complex I protein (KO). KO increased glycolysis and reduced oxygen consumption in bone marrow derived macrophage (BMDM), and demonstrated exacerbated inflammatory response to LPS stimulation. In mice with myeloid-specific deletion of Ndufs4 (mKO) we showed increased mortality and poor cardiac function after MI. These observations led us to hypothesize that mitochondrial function is a key regulator of macrophage polarization during post-MI remodeling and hence a potential therapeutic target. To test the hypothesis, we will investigate the mechanistic link between mitochondrial function and epigenetic reprogramming during stimulation in primary macrophages, and furthermore, test the effects of manipulating mitochondrial function in macrophage function and post-MI remodeling in mice.

摘要

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Role of Innate Immune Cells in Cardiac Injury and Repair: A Metabolic Perspective.

DOI：
10.1007/s11886-023-01897-4
发表时间：
2023-07
期刊：
CURRENT CARDIOLOGY REPORTS
影响因子：
3.7
作者：
Banerjee, Durba;Tian, Rong;Cai, Shanshan
通讯作者：
Cai, Shanshan

Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes.

DOI：
10.1172/jci139828
发表时间：
2022-03-01
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Wu J;Singh K;Lin A;Meadows AM;Wu K;Shing V;Bley M;Hassanzadeh S;Huffstutler RD;Schmidt MS;Blanco LP;Tian R;Brenner C;Pirooznia M;Kaplan MJ;Sack MN
通讯作者：
Sack MN

Boosting mitochondrial metabolism with dietary supplements in heart failure.