Immunometabolism and Macrophage Function

Immunometabolism investigates the interplay between cellular metabolism and immune cell function, with macrophages serving as a paradigm for this relationship. These versatile cells adopt distinct activation states in response to environmental cues: pro-inflammatory macrophages preferentially engage aerobic glycolysis, leading to rapid ATP production and accumulation of metabolites such as succinate and itaconate, which reinforce inflammatory signalling. In contrast, anti-inflammatory or tissue-repair macrophages rely on oxidative phosphorylation and fatty acid oxidation, maintaining an intact tricarboxylic acid cycle to support longer-term functions. Metabolic intermediates not only supply energy and biosynthetic precursors but also directly modulate epigenetic and transcriptional programmes. This metabolic plasticity underlies macrophage roles in host defence, wound healing, tumour progression and chronic inflammatory diseases. By elucidating how nutrient sensing and metabolic pathways shape macrophage phenotypes, immunometabolism offers novel avenues for therapeutic intervention aimed at re-educating macrophages in cancer, atherosclerosis, obesity and autoimmune conditions.

Research from Nature Portfolio

Recent studies have demonstrated that activation of the costimulatory receptor CD40 remodels macrophage metabolism by promoting fatty acid oxidation and glutamine utilisation, thereby driving epigenetic reprogramming of pro-inflammatory and anti-tumourigenic genes. In parallel, work on nitric oxide has revealed that this metabolite targets mitochondrial aconitase and pyruvate dehydrogenase, rerouting carbon flux away from the tricarboxylic acid cycle and inducing glutamine-dependent anaplerosis to shape classical activation. Additionally, adaptive glycolytic reprogramming mediated by hypoxia-inducible factor-1α and pyruvate dehydrogenase kinase 1 has been shown to support macrophage migratory capacity under mild hypoxia, linking metabolic control to cellular motility and systemic inflammatory responses.

Immunometabolism and Macrophage Function publication trend

The graph below shows the total number of articles in immunometabolism and macrophage function across all publications each year (not limited to Nature Index journals).

Technical terms

Immunometabolism: The study of how metabolic processes influence immune cell function and fate.

Glycolysis: A cytosolic pathway that converts glucose to pyruvate, generating ATP rapidly under inflammatory conditions.

Oxidative phosphorylation: A mitochondrial process that produces ATP via the electron transport chain, supporting long-term cellular functions.

Tricarboxylic acid cycle: A series of enzymatic reactions in mitochondria that oxidise acetyl-CoA to generate reducing equivalents for energy production.

Fatty acid oxidation: The mitochondrial breakdown of fatty acids to acetyl-CoA, fuelling oxidative phosphorylation in anti-inflammatory macrophages.

Anaplerosis: The replenishment of tricarboxylic acid cycle intermediates, often via glutamine metabolism, to sustain biosynthesis and energy generation.

Macrophage polarisation: The process by which macrophages adopt diverse functional states, commonly simplified into pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes.

References

1. CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions. Nature Immunology (2023).
2. Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase. Nature Communications (2020).
3. HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity. Nature Communications (2016).
4. The Metabolic Signature of Macrophage Responses. Frontiers in Immunology (2019).
5. Macrophage Metabolism As Therapeutic Target for Cancer, Atherosclerosis, and Obesity. Frontiers in Immunology (2017).
6. New Insights on the Role of Lipid Metabolism in the Metabolic Reprogramming of Macrophages. Frontiers in Immunology (2020).