Dynamic Metabolic Reprogramming in Macrophages during Immune Response

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Project Summary / Abstract The overarching goal of this project is to understand how cellular metabolism is dynamically reprogrammed in macrophages during immune responses, and how such metabolic reprogramming impacts immune functions. Emerging research indicates that metabolism plays a crucial role in supporting and orchestrating immunity. However, our understanding of macrophage metabolism is just beginning, and is largely limited to static comparisons of metabolic preferences associated with different activation states. Understanding time-dependent metabolic rewiring is of great significance because an immune response is a highly dynamic process, through which macrophages undergo a sequence of functional transitions that mediate the onset and resolution of inflammation. Proper regulation of macrophage responses is critical, as failure to activate or control macrophage functions at the appropriate times can lead to a variety of diseases. The integrative approach that we take to investigate dynamic metabolic rewiring during an immune response starts with a multi-omics characterization that reveals metabolic processes whose alteration is temporally coupled to functional transitions. This is followed by targeted perturbations to determine the impact of these metabolic alterations on immune functions. Then we perform isotopic tracing studies to quantitatively characterize how fluxes through these pathways change during immune responses and identify important regulatory points. Finally, in-depth molecular studies are used to elucidate the mechanisms driving these key metabolic alterations and the mechanisms by which such metabolic alterations orchestrate immune functions. Our preliminary work on the dynamic metabolic rewiring in macrophages upon LPS and interferon-γ stimulation revealed that alterations in TCA cycle and nucleotide metabolism are critical for this immune response. We discovered that metabolic fluxes through the TCA cycle undergo a two-stage remodeling and that inhibition of the pyruvate dehydrogenase complex (PDHC) drives the transition from early inflammatory stage to late suppressive stage. Building on this, aim 1 will investigate the molecular mechanism causing PDHC inhibition, and test the hypothesis that PDHC inhibition drives the transition into a more suppressive state and mediates immune tolerance by restricting acetyl-coA for histone acetylation. Aim 2 will focus on nucleotide metabolism to quantitatively study how nucleotide synthesis, degradation, and salvage fluxes change upon LPS and interferon-γ stimulation, and elucidate the mechanism driving such changes. Aim 3 will expand the scope of this proposal by characterizing the dynamic metabolic reprograming in response to a variety of other stimuli using multi-omics approaches. It will identify key metabolic transitions in each response and create a roadmap towards mechanistic understanding of the metabolism-immunity coupling. Overall, this proposal will elucidate the metabolic underpinnings of immune responses in macrophages, which has great importance in basic science and broad relevance to diseases where macrophages play a key role.