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.
The proposed study will determine the metabolic mechanisms that modulate macrophage function. We will first, test the hypothesis that mitochondrial function is a key regulator of macrophage phenotype post myocardial infarction (MI) and second, evaluate the potential of targeting mitochondrial function in macrophage as a therapy for post-MI remodeling.
