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Krebs Cycle Reborn in Macrophage Immunometabolism
Dylan G Ryan1, Luke A J O'Neill1
1School of Biochemistry and Immunology and Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland;
Insights
Immune cell activation is critically determined by metabolic processes, particularly the Krebs cycle in macrophages. Metabolites like succinate and itaconate signal inflammatory gene expression, offering therapeutic targets for inflammatory diseases.
Area of Science:
- Immunology
- Metabolism
- Cell Biology
Background:
- Metabolic processes are critical determinants of immune cell activation.
- Immune receptors rewire metabolic pathways to promote effector functions.
- The Krebs cycle is a central immunometabolic hub in macrophages.
Purpose of the Study:
- To review advances in immunometabolism.
- To discuss the role of the Krebs cycle in macrophage activation.
- To explore therapeutic targeting of immunometabolic pathways for inflammatory diseases.
Main Methods:
- Review of current literature on immunometabolism.
- Analysis of metabolic pathways in activated macrophages.
- Discussion of signaling roles of metabolic intermediates.
Main Results:
- Proinflammatory macrophages accumulate Krebs cycle intermediates (succinate, citrate, itaconate) that influence gene expression.
- Electron transport chain alterations generate reactive oxygen species.
- Alternatively activated macrophages utilize α-ketoglutarate for epigenetic reprogramming.
Conclusions:
- Metabolic reprogramming is integral to macrophage activation and function.
- Specific metabolites act as signaling molecules influencing inflammation.
- Targeting immunometabolic pathways presents a potential therapeutic strategy for inflammatory conditions.
Abstract:
A striking change has happened in the field of immunology whereby specific metabolic processes have been shown to be a critical determinant of immune cell activation. Multiple immune receptor types rewire metabolic pathways as a key part of how they promote effector functions. Perhaps surprisingly for immunologists, the Krebs cycle has emerged as the central immunometabolic hub of the macrophage. During proinflammatory macrophage activation, there is an accumulation of the Krebs cycle intermediates succinate and citrate, and the Krebs cycle-derived metabolite itaconate. These metabolites have distinct nonmetabolic signaling roles that influence inflammatory gene expression. A key bioenergetic target for the Krebs cycle, the electron transport chain, also becomes altered, generating reactive oxygen species from Complexes I and III. Similarly, alternatively activated macrophages require α-ketoglutarate-dependent epigenetic reprogramming to elicit anti-inflammatory gene expression. In this review, we discuss these advances and speculate on the possibility of targeting these events therapeutically for inflammatory diseases.
