Metabolic Reprogramming of Macrophage During Inflammation Resolution and Cardiac Wound Healing

Zhang, Shuang

doi:https://doi.org/10.21985/n2-g5a1-gy20

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Metabolic Reprogramming of Macrophage During Inflammation Resolution and Cardiac Wound Healing

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Macrophages are one of the most versatile immune cells in the immune system. They are found in nearly every tissue and organ throughout the body. Macrophages play important roles of orchestrating initiation and resolution of inflammation, such as sentineling against pathogens or engulfing apoptotic cells. Macrophages are able to respond to a variety of different stimuli and secret an array of different cytokines in response to different stimuli, which can further license a large amount of other types of cells such as B cells, T cells, neutrophils, or fibroblasts. Thus, this thesis work has been dedicated to elucidating the mechanisms that orchestrate macrophage activation. Each day billions of cells per person turns over during normal homeostatic process or tissue injuries. One of the most important roles of macrophage is clearing dying cells (a process termed efferocytosis). Different from phagocytosis of bacteria, upon efferocytosis, macrophages reprogram to a resolving status where they secret anti-inflammatory and pro-resolving factors such IL10 and TGFβ while reduce anti-inflammatory cytokine secretion, such as TNFα and IL1β. However, when efferocytosis is ineffective, it can lead to prolonged inflammation, delayed wound healing, and auto-immune disorders. More importantly, we found that efferocytosis also plays an important role in wound healing in the heart. Heart failure after myocardial infarction is a significant cause of morbidity and mortality. During MI, a burst of cardiomyocyte (CM) triggers recruitment and mobilization of phagocytic monocytes and macrophages that clear myocardial tissue. While prompt phagocytic clearance of dying cardiomyocytes triggers homeostatic tissue remodeling via anti-inflammatory and pro-reparative signaling pathways within phagocyte, delayed phagocytosis lead to maladaptive tissue repair which can lead to heart failure. Thus, it is of great importance to identify the orchestrating machineries that regulate the anti-inflammatory reprogramming in macrophages after efferocytosis. It is now well appreciated that intracellular metabolism is integrated with the balance of cell activation and function. In macrophages, glycolysis is required for pro-inflammatory (M1) cell activation and the mobilizing of biosynthetic precursors to combat bacterial infection, while fatty acid oxidation is more required for alternative macrophage (M2) polarization. In the case of efferocytosis, macrophages not only receive anti-inflammatory signaling initiated by apoptotic cell/scavenger receptor contact, but also bring extracellular macromolecules such as lipids into efferocytes. How do macrophages metabolically respond to such stimuli awaits to be discovered. We found that apoptotic cells with different fatty acid loads initiate anti-inflammatory response in macrophages to different degrees. Using a mouse model in which myeloid lineage specific deletion of complex III protein RISP leads to reduced anti-inflammatory IL10 secretion from macrophages after efferocytosis. Myeloid RISP deficiency mice also showed defected wound healing/recover after myocardial infarction. Thus, we elucidated a key role of mitochondrial electron transport chain in efferocytosis mediated macrophage reprogramming. We also found that ETC facilitate IL10 production via regulating NAD+/NADH level in macrophages. This further led to SIRT1 activation. These findings highlight a key role for mitochondria/SIRT1 pathway in regulating macrophage reprogramming after efferocytosis and suggest how metabolism can fine-tune macrophage functions during cardiac wound healing.

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