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Immunometabolism: Metabolism and the Immune System

Immunometabolism describes the interaction between metabolic processes and the immune system, shaping immune responses in conditions such as diabetes, cancer, and autoimmune diseases.

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Things worth knowing about "Immunometabolism"

Immunometabolism describes the interaction between metabolic processes and the immune system, shaping immune responses in conditions such as diabetes, cancer, and autoimmune diseases.

What Is Immunometabolism?

Immunometabolism is a rapidly growing field of biomedical research that investigates the close relationship between metabolism and the immune system. Recognized as an independent discipline since around 2010, it examines how metabolic pathways control the activation, differentiation, and function of immune cells – and conversely, how immune activity shapes the metabolic state of tissues and the whole body.

The Link Between the Immune System and Metabolism

Immune cells such as macrophages, T lymphocytes, dendritic cells, and natural killer cells require energy to perform their functions. Depending on their activation state and role, they rely on distinct metabolic pathways:

Glycolysis: Rapid energy production from glucose, preferred by pro-inflammatory immune cells.
Oxidative phosphorylation (OXPHOS): More efficient, mitochondria-based energy production, characteristic of anti-inflammatory and regulatory cells.
Fatty acid oxidation: Use of fats as fuel, important for long-lived memory immune cells.
Glutaminolysis: Metabolism of the amino acid glutamine, critical for cell growth and immune activation.

These pathways are not fixed but adapt dynamically to the demands of the immune cell at any given moment. This adaptability is referred to as metabolic plasticity.

Immunometabolism in Chronic Disease

Dysregulation of immunometabolism plays a central role in the development and progression of many chronic conditions:

Type 2 Diabetes and Obesity

In obesity, adipose tissue macrophages produce elevated levels of pro-inflammatory signaling molecules (cytokines such as TNF-α and IL-6). This chronic, low-grade inflammation disrupts insulin signaling in muscle, liver, and fat cells, contributing to insulin resistance – a hallmark of type 2 diabetes.

Cancer

Tumor cells actively remodel their metabolic environment to evade immune destruction. They consume large amounts of glucose (the Warburg effect) and create an immunosuppressive microenvironment that impairs T cell function. Understanding these mechanisms underpins the development of modern cancer immunotherapies.

Autoimmune Diseases

In diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, immune cells exhibit abnormal metabolic programming. For example, auto-reactive T cells display elevated glycolysis rates, which drives their excessive activation and tissue damage.

Infectious Diseases

Pathogens such as bacteria and viruses actively interfere with immune cell metabolism to suppress host defense. Conversely, the immune system leverages metabolic processes to eliminate pathogens – for example, by generating reactive oxygen species (ROS) in activated macrophages.

Key Molecules in Immunometabolism

Several molecules and signaling pathways act as critical regulators:

mTOR (mechanistic Target of Rapamycin): A central nutrient and energy sensor that governs immune cell activation and differentiation.
AMPK (AMP-activated protein kinase): An energy sensor that activates anti-inflammatory programs when cellular energy is low.
HIF-1α (Hypoxia-inducible factor 1-alpha): Promotes glycolysis and pro-inflammatory responses in immune cells under low-oxygen conditions.
Succinate and itaconate: Metabolic intermediates that act directly as intracellular signaling molecules in immune cells.
NAD+ / NADH ratio: Influences epigenetic regulation and gene expression in immune cells.

Clinical Relevance and Therapeutic Approaches

Insights from immunometabolism research are opening new avenues for treating a wide range of diseases. Therapeutic strategies aim to selectively modulate the metabolism of immune cells:

Metformin: A widely used diabetes drug that activates AMPK, dampening inflammatory processes and potentially offering benefits in cancer prevention.
mTOR inhibitors (e.g., rapamycin): Suppress excessive immune activation and are used in transplantation medicine and autoimmune conditions.
Immune checkpoint inhibitors: Reinvigorate metabolically exhausted T cells within the tumor microenvironment.
Dietary interventions: Caloric restriction, intermittent fasting, and ketogenic diets demonstrably alter immune metabolism and can modulate inflammatory processes.

References

O'Neill, L.A.J., Kishton, R.J., Rathmell, J. - A guide to immunometabolism for immunologists. Nature Reviews Immunology, 2016; 16(9): 553–565.
Ganeshan, K., Chawla, A. - Metabolic regulation of immune responses. Annual Review of Immunology, 2014; 32: 609–634.
Pearce, E.L., Pearce, E.J. - Metabolic pathways in immune cell activation and quiescence. Immunity, 2013; 38(4): 633–643.

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