The Crucial Connection Between Metabolism and the Immune System.
Over the past couple of decades, immunology has grown at an exponential pace. Today, immunologists who study intracellular and extracellular immune components are also developing new therapies that suppress the immune system, boost it, or correct its dysregulation. At the same time, researchers have increasingly studied organism-level and intracellular metabolism in diseases like diabetes and cancer. This has led to a growing focus on how immune cells’ own intracellular metabolism shapes their phenotype and activation, and how the immune system in turn affects the host organism’s metabolism — a field known as immunometabolism1.
Cells use several metabolic pathways to make ATP. Researchers have found that some cells preferentially use the glycolytic pathway to make ATP, even when the components needed for aerobic respiration are available — a phenomenon called the Warburg effect1. Other cells combine the glycolytic pathway with the Krebs cycle and electron transport chain (ETC), a process known as oxidative phosphorylation (OxPhos), to convert materials into energy1.
Not all immune cells behave alike, though. Activated neutrophils preferentially use the Warburg effect1. Interestingly, this pathway produces the most hydrogen peroxide, which neutrophils use in granulocytic release against pathogens1. Similarly, dendritic cells activated through a toll-like receptor agonist, and that express inducible nitric oxide synthase (iNOS), also rely on the Warburg effect — and as in neutrophils, iNOS’s metabolite plays a functional role in these activated dendritic cells1. M1 pro-inflammatory macrophages use the Warburg pathway too1.
Glycolysis and oxidative phosphorylation connect when the pyruvate from glycolysis feeds into the Krebs cycle to make acetyl-CoA. Immune cells that use this combined pathway include activated T-cells, immunosuppressive M2 macrophages, and pro-inflammatory Th17 T-cells1. Finally, fatty acid oxidation — using lipids to make ATP — powers memory T-cells, regulatory T-cells, and alternatively-activated macrophages1.
Metabolism Shapes More Than Just Cell Activation
Metabolism does more than influence a cell’s activation state. It also plays a role in the homeostasis between immune cells, and between immune cells and their stromal host cells1. Researchers have found dysregulated metabolites in many diseases, and actively study how much of that metabolite fluctuation comes from the host’s immune cells versus from pathogens2. Metabolism also helps drive the switch from effector T-cells to memory T-cells, and plays a role in bringing immune cells into quiescence3.
One compelling example of the link between immunity and metabolism appeared in an article published in Nature on April 11, 2013, by Tannahill et al. This paper shows that the metabolite succinate — a key component of the Krebs cycle — plays an integral role in lipopolysaccharide-induced macrophage activation4. The researchers also showed that activating toll-like receptor 4 through LPS stimulation increases intracellular glutamate uptake and boosts succinate production through the “gamma-Aminobutyric acid (GABA) shunt” metabolic pathway4. The resulting succinate then stabilizes hypoxia-inducible factor-1α; a protein involved in IL-1β production4.
Why Immunometabolism Matters for Future Therapies
Studying metabolism isn’t just an academic exercise. Researchers have proposed many therapies that target the metabolic system to correct dysregulated immune responses. One example is metformin, a drug used to help manage type 2 diabetes2. Researchers are now also actively investigating metformin as an anti-cancer therapeutic, since it can shift the tumor immune microenvironment from a pro-tumor phenotype toward an anti-tumor one2. As we learn more about how host metabolism affects the immune system, how the immune system affects organism metabolism, and which intracellular metabolic pathways drive various immune cells through different functional states, we’ll hopefully be able to develop more therapies that repair immune dysregulation and treat metabolic diseases through immune-targeted approaches.
Further Reading
1. Pearce, E. L. & Pearce, E. J. Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633-643, doi:10.1016/j.immuni.2013.04.005 (2013).
2. Mathis, D. & Shoelson, S. E. Immunometabolism: an emerging frontier. Nature reviews. Immunology 11, 81, doi:10.1038/nri2922 (2011).
3. Finlay, D. & Cantrell, D. A. Metabolism, migration and memory in cytotoxic T cells. Nature reviews. Immunology 11, 109-117, doi:10.1038/nri2888 (2011).
4. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496, 238-242, doi:10.1038/nature11986 (2013).
