A Guide to Immunometabolism

As the name suggests, immunometabolism is an emerging field of science that is associated with immunology and metabolism. Many scientists have shown their interest in this field owing to the current surge in obesity across the globe, known as the obesity epidemic. Obesity impacts the immune system, which subsequently triggers inflammation. Scientists have found that obesity-induced inflammation results in various chronic diseases.

Metabolism Concept

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Metabolism and immunity

All multicellular organisms possess two fundamental characteristics, which are, (a) the requirement to effectively distribute nutrition across all cells and tissues and (b) to protect from harmful foreign invaders, such as viruses, bacteria, etc., and injury. Hence, the link between immunity and metabolism is very much expected.

Scientists have revealed that metabolites and the activation of metabolic pathways are involved with the production of energy, intracellular signaling, macromolecule synthesis, post-translational modifications, and cell survival.

A recent study has reported that inflammation is connected with many pathologies of metabolic syndrome. An individual suffering from malnutrition is known to be immune suppressive.

In 1993, Hotamisligil and his team of researchers at the Dana-Farber Cancer Institute, Boston, reported that adipose tissue produced tumor necrosis factor-alpha (TNFα) while studying the murine models of obesity and diabetes. This research showed that over-nutrition can stimulate inflammation which causes insulin resistance, and consequently, result in chronic conditions like diabetes and metabolic syndrome.

Scientists have reported that both the metabolism of immune cells and metabolic tissues regulating immune cells are highly organized. In a previous study, researchers found that aerobic glycolysis in cancer cells and metabolism of immune cells is triggered by activated oncogenic signaling pathways.

Another study revealed that macrophage metabolism (metabolic program) can trigger the synthesis of inflammatory cytokines.

Overview of immunometabolism

The mid-way metabolic and immune system interaction leads to many downstream complications of obesity. This field of science describes the changes that take place in the intracellular metabolic pathways in immune cells after stimulation. Scientists have shown various major pathways in immune cells.

Some of these metabolic pathways include glycolysis, the pentose phosphate pathway, fatty acid synthesis, the tricarboxylic acid (TCA) cycle, amino acid metabolism, and fatty acid oxidation.

Among these, two metabolic pathways play a major role in the activation of macrophages via lipopolysaccharide (LPS), which are glycolysis and fatty acid synthesis. However, the activation of macrophages based on interleukin-4 (IL-4), metabolic pathways, such as oxidative phosphorylation and fatty acid oxidation are used for the generation of energy. Further, recent studies have revealed that effector T cells are highly glycolytic, whilst memory T cells possess oxidative metabolism.

Scientists have discovered some of the metabolites that have functions beyond metabolism, i.e., they are also involved in the specific events during cell activation. Some of these metabolites are succinate and citrate.

Similarly, enzymes that play an essential role in immune systems are pyruvate kinase isoenzyme M2 (PKM2), enolase, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Also, researchers have reported that small molecules can target metabolic pathways and can modify the phenotype of immune cells.

Metabolic pathways that regulate immune metabolism

Scientists have shown great interest in understanding the metabolism of cytotoxic T cells as they can be used to design various therapeutics and biologicals. A large body of research has been directed towards the uptake and metabolism of amino acids mainly glutamine, glucose, and some fatty acids. However, many other metabolites influence metabolism.

Scientists revealed that when T cells are triggered through the antigen receptor, co-stimulation of Cluster of Differentiation 28 (CD28) occurs. This results in the increase of glucose transporter GLUT1 expression, glucose uptake, and subsequent glycolysis and promotes mitochondrial metabolism.

In contrast, CD28 family inhibitory receptors, namely, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death-1 (PD-1) can inhibit this metabolic transition. In the condition when T cells fail to receive CD28 co-stimulation, it becomes anergic and is metabolically suppressed.

Scientists also reported that although effector T cells induce aerobic glycolysis, memory T cells depend on mitochondrial metabolism and lipid oxidation. However, they can rapidly revert to glycolysis upon re-stimulation via endoplasmic reticulum-mitochondrial direct interactions. In contrast to effector T cell subsets, regulatory T cells (Tregs) do not require GLUT1 or high levels of glutamine uptake via amino acid transporter ASCT2. Tregs mainly rely on mitochondrial lipid, pyruvate, and lactate oxidation.

Similar to that of T cells, B cell activation and cytokine stimulation stimulate glycolysis. However, flux through the pentose phosphate pathway can suppress B cells and mitochondrial activity which in turn control apoptosis. A dynamic microenvironment can drive glycolysis and modify B cell proliferation and fate. It is pivotal to understand the pathways that regulate B cell metabolism which could help differentiate between a normal B cell function and B cell transformation due to leukemia and lymphoma.

Scientists have revealed that B cells have precise metabolic demands to assist high rates of protein synthesis. However, the metabolic demand related to plasmablasts and long-lived plasma cells is not yet understood.

Innate immune cells also undertake metabolic programming and use metabolic pathways to control cell fate. Mononuclear phagocytes play an important role in bridging innate and adaptive immunity. The interactions are controlled via cell metabolisms which regulate inflammatory responses. Dendritic cells display a short spell of oxidative phosphorylation (OXPHOS) on lipopolysaccharide (LPS) stimulation.

After a few hours, the cells are downregulated and are engaged in aerobic glycolysis. The macrophages undergo analogous metabolic reprogramming after encountering a danger signal activation, such as LPS.

Disease and immunometabolism

Scientists have discovered that viral infection can modify cholesterol synthesis. They found that the microenvironment of the lungs consists of barrier cells and immune regulatory mechanisms to maintain homeostasis and protect the body against pathogens. Influenza virus can elicit metabolic reprogramming of both immune and epithelial cells.

Influenza-induced metabolic reprogramming in the epithelial cells is led by the activation of the PI3K/mTOR/Akt pathway. Also, influenza infection is associated with immune cell populations such as dendritic cells, natural killer (NK) cells, macrophages, and T cells. For instance, this virus influences dendritic cells to undergo hyperglycolysis with relatively low oxygen utilization.

Sources:

  • Voss, K. et al. (2021). A guide to interrogating immunometabolism. Nature Reviews Immunology. https://doi.org/10.1038/s41577-021-00529-8
  • Makowski, L. et al. (2020). Immunometabolism: From basic mechanisms to translation. Immunological Reviews, 295, pp. 5-14. DOI: 10.1111/imr.12858
  • Mathis, D., and Shoelson, S.E. (2011). Immunometabolism: an emerging frontier. Nature Reviews Immunology, 11(2), pp. 81. https://doi.org/10.1038/nri2922
  • O'Neill, L. et al. (2016). A guide to immunometabolism for immunologists. Nature Reviews Immunology, 16, pp. 553-565 https://doi.org/10.1038/nri.2016.70

Further Reading

Last Updated: Oct 5, 2021

Dr. Priyom Bose

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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