Immunometabolic circuits in trained immunity

- Trained immunity represents a de facto memory of the innate immune system.
- Induction of trained immunity is accompanied by significant changes in cellular metabolism.
- Increased glycolysis is a central hallmark of trained macrophages.
- Accumulation of several metabolites could lead to modulation of the epigenetic landscape.
- Targeting immunometabolism is a promising therapeutic intervention.

The classical view that only adaptive immunity can build immunological memory has recently been challenged. Both in organisms lacking adaptive immunity as well as in mammals, the innate immune system can adapt to mount an increased resistance to reinfection, a de facto innate immune memory termed trained immunity. Recent studies have revealed that rewiring of cellular metabolism induced by different immunological signals is a crucial step for determining the epigenetic changes underlying trained immunity. Processes such as a shift of glucose metabolism from oxidative phosphorylation to aerobic glycolysis, increased glutamine metabolism and cholesterol synthesis, play a crucial role in these processes. The discovery of trained immunity opens the door for the design of novel generations of vaccines, for new therapeutic strategies for the treatment of immune deficiency states, and for modulation of exaggerated inflammation in autoinflammatory diseases.