Metabolic Regulation of Inflammation in Immune Cells

Immune cells undergo profound metabolic reprogramming during activation, linking bioenergetic pathways to inflammatory outcomes. In macrophages and dendritic cells, engagement of pattern recognition receptors induces a shift from oxidative phosphorylation towards aerobic glycolysis, providing rapid ATP and biosynthetic precursors while generating immunoregulatory metabolites. Key tricarboxylic acid (TCA) intermediates—including citrate, succinate and malate—function as signalling hubs that modulate transcription factors, enzyme activities and post-translational modifications. In parallel, anti-inflammatory metabolites such as itaconate accumulate via the enzyme encoded by immunoresponsive gene 1 (IRG1), suppressing succinate dehydrogenase and dampening pro-inflammatory cytokine release. In adaptive lymphocytes, metabolic pathways coordinate effector and regulatory cell fates: glycolysis and oxidative phosphorylation balance supports differentiation of inflammatory Th17 cells or anti-inflammatory Treg cells, respectively, and metabolic cues influence chromatin accessibility to shape gene expression. Central sensors such as mTOR, HIF1α and AMP-activated protein kinase integrate nutrient availability with inflammatory programmes. Collectively, metabolic regulation of inflammation in immune cells underpins host defence, tolerance and tissue repair, and offers avenues for therapeutic modulation in autoimmunity, infection and cancer.

Research from Nature Portfolio

Recent studies have elucidated how itaconate orchestrates metabolic and epigenetic networks in T cells to ameliorate autoimmunity. Itaconate suppresses both glycolysis and oxidative phosphorylation in Th17- and Treg-polarizing lymphocytes, altering the balance of methyl donors and oncometabolites to reshape chromatin accessibility at lineage-defining loci. This reprogramming reduces RORγt binding at pro-inflammatory genes while promoting Foxp3 expression, and adoptive transfer of treated cells mitigates experimental autoimmune encephalomyelitis. In macrophages, a cell-permeable derivative of itaconate directly alkylates the glycolytic enzyme GAPDH, halting aerobic glycolysis and curbing cytokine production. This mechanism underlies protection from lipopolysaccharide-induced lethality and demonstrates how targeted modification of a single metabolic enzyme can exert systemic anti-inflammatory effects.

Metabolic Regulation of Inflammation in Immune Cells publication trend

The graph below shows the total number of articles in metabolic regulation of inflammation in immune cells across all publications each year (not limited to Nature Index journals).

Technical terms

Itaconate: A macrophage-derived metabolite produced by IRG1 that modulates inflammation via enzyme inhibition and transcriptional control.

Glycolysis: The cytosolic pathway converting glucose to pyruvate, supplying ATP and biosynthetic intermediates for immune activation.

Oxidative phosphorylation: Mitochondrial ATP production via the electron transport chain, whose activity is adjusted during immune responses.

Tricarboxylic acid (TCA) cycle: Central metabolic pathway generating intermediates that serve both as energy carriers and signalling molecules in immune cells.

NLRP3 inflammasome: A multiprotein complex that activates inflammatory caspases and cytokine secretion in response to metabolic and danger signals.

Epigenetic reprogramming: Alterations in chromatin structure and histone modifications driven by metabolic intermediates that govern immune gene expression.

References

1. Malate initiates a proton-sensing pathway essential for pH regulation of inflammation. Signal Transduction and Targeted Therapy (2024).
2. Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance. Cancer Cell (2024).
3. Itaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming. Nature Communications (2023).
4. Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels*. Journal of Biological Chemistry (2016).
5. A Role for the Krebs Cycle Intermediate Citrate in Metabolic Reprogramming in Innate Immunity and Inflammation. Frontiers in Immunology (2018).
6. 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects. Nature Communications (2019).
7. The role of itaconate in host defense and inflammation. Journal of Clinical Investigation (2022).