Regulation of Inflammatory Macrophage Activation and Tolerance by Modulation of Glucose Metabolism
Citation
Langston, Paul Kent. 2019. Regulation of Inflammatory Macrophage Activation and Tolerance by Modulation of Glucose Metabolism. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.Abstract
The reactions in an organism’s metabolic network take on dynamic changes in fluxes in response to imposed stress to support calibrated functional responses. Macrophages, phagocytic cells of the myeloid lineage, are activated during microbial infection to coordinate inflammatory responses and host defense. Here we show that in macrophages activated by bacterial lipopolysaccharide (LPS), mitochondrial glycerol 3-phosphate dehydrogenase (GPD2) regulates glucose oxidation to drive inflammatory responses. GPD2, a component of the glycerol phosphate shuttle (GPS), boosts glucose oxidation to fuel acetyl-CoA (Ac-CoA) production, histone acetylation and inflammatory gene induction. While acute LPS exposure drives macrophage activation, prolonged exposure triggers entry into LPS tolerance, where macrophages orchestrate immunosuppression to limit the detrimental effects of sustained inflammation. We find that the shift from activation to tolerance is modulated by GPD2, which coordinates a shutdown of oxidative metabolism that limits Ac- CoA availability for histone acetylation at inflammatory genes, thus contributing to suppression of inflammatory responses. Therefore, GPD2 and the GPS integrate the extent of microbial stimulation with glucose oxidation to balance the beneficial and detrimental effects of the inflammatory response. In addition, we show that LPS-inducible glucose oxidation is downstream of the serine/threonine kinase Akt. We find that Akt signaling controls glucose oxidation to couple the strength and duration of LPS exposure to the GPD2-dependent increase and decrease in mitochondrial respiration, promoter region histone acetylation, and inflammatory gene induction in macrophages over the transition from activation to tolerance. Furthermore, transcriptional profiling of tolerant macrophages re-exposed to LPS revealed a subset of highly-responsive, primed (P) genes, important for antimicrobial activity and mitochondrial respiration. Induction of P genes is Akt-dependent and fueled by acetate-derived Ac-CoA production catalyzed by nucleocytosolic Ac-CoA synthetase (ACSS2) rather than by citrate-derived Ac-CoA from glucose oxidation. Therefore, Akt and ACSS2 act as additional regulatory modules integrating TLR signaling with shifts in macrophage metabolism to induce gene-specific responses to microbial encounter. Taken together, our findings support a paradigm shift in immunometabolism, demonstrating that glucose oxidation regulates induction and suppression of macrophage inflammatory responses while also identifying several novel metabolic pathways controlling gene- specific transcriptional responses in tolerant macrophages.Terms of Use
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