Discover how mTOR- and HIF-1α-mediated aerobic glycolysis serves as the metabolic basis for trained immunity, revolutionizing our understanding of immune memory.
Think of your immune system like an athlete training for competition. The first time it encounters a pathogen, it doesn't just fight off the immediate threat—it actually builds cellular "muscle memory" that prepares it for future challenges.
For decades, scientists believed this memory capability existed only in the specialized adaptive immune system. But groundbreaking research has revealed a surprising truth: even the innate immune system—our body's first responder—can build a form of memory. This phenomenon, dubbed "trained immunity," represents a paradigm shift in immunology 8 .
Even more astonishing, the source of this cellular memory lies not in specialized immune receptors, but in the fundamental metabolic processes that power our cells, specifically through a pathway involving mTOR and HIF-1α that switches immune cells into a high-glycolysis state 8 .
Provides immediate, non-specific defense against pathogens, acting as a first responder that was traditionally thought to lack memory.
Offers highly specific, long-lasting protection through antibodies and memory cells that recognize previously encountered pathogens 3 .
Trained immunity shatters this simple dichotomy. It refers to the ability of innate immune cells like monocytes and macrophages to develop enhanced responsiveness after an initial encounter with a pathogen, providing non-specific protection against subsequent infections 8 .
| Feature | Adaptive Immune Memory | Trained Immunity |
|---|---|---|
| Cells involved | T and B lymphocytes | Monocytes, macrophages, NK cells, possibly stem cells |
| Specificity | Highly specific to antigens | Broad, non-specific protection |
| Duration | Years to lifetime | Months to a few years |
| Molecular basis | Gene rearrangement, clonal expansion | Epigenetic and metabolic reprogramming |
| Metabolic requirements | Not well-characterized | Dependent on mTOR/HIF-1α-mediated glycolysis |
How do short-lived innate immune cells maintain memory? The answer lies in two interconnected processes: epigenetic reprogramming and metabolic rewiring.
Ordinarily, most cells prefer to generate energy through oxidative phosphorylation in mitochondria—an efficient process that maximizes ATP yield from glucose. But trained immune cells switch to aerobic glycolysis, a far less efficient pathway that burns through glucose rapidly while producing lactate 2 .
The answer lies in speed and biosynthetic capacity. Aerobic glycolysis allows rapid ATP production and generates metabolic intermediates that feed into biosynthetic pathways, supporting the production of proteins, lipids, and nucleic acids needed for enhanced immune function 2 .
Immune cells encounter β-glucan through their dectin-1 receptors
Triggers Akt phosphorylation, which activates mTOR—a central regulator of cellular metabolism 2
Reprogrammed metabolism creates fuel needed to maintain epigenetic changes
While trained immunity evolved to enhance host defense, it can sometimes backfire. The same mechanisms that protect against infection can contribute to chronic inflammatory diseases 8 . For instance, oxidized LDL cholesterol can train innate immune cells, potentially exacerbating atherosclerosis 3 .
Human primary monocytes exposed to β-glucan for 24 hours
Cells washed and maintained in culture for six days
Cells restimulated with LPS and response measured 2
| Metabolic Parameter | Naive Monocytes | β-Glucan-Trained Monocytes | Significance |
|---|---|---|---|
| Glucose consumption | Baseline | Increased ~2-fold | More fuel for rapid response |
| Lactate production | Baseline | Increased ~2.5-fold | Shift to aerobic glycolysis |
| NAD+/NADH ratio | Baseline | Significantly elevated | Altered redox state affecting enzyme activity |
| Oxygen consumption rate | Baseline | Reduced by ~30% | Decreased mitochondrial metabolism |
| Intervention | Target | Effect on Trained Immunity | Implications |
|---|---|---|---|
| Rapamycin | mTOR | Complete blockade | Demonstrates mTOR necessity |
| Ascorbate | HIF-1α | Dose-dependent inhibition | Shows HIF-1α critical role |
| 2-deoxy-D-glucose | Glucose metabolism | Prevents training | Confirms metabolic dependence |
| AICAR | AMPK activation | Inhibits training | Highlights energy sensing role |
| Dectin-1 deficiency | β-glucan receptor | Abolishes training | Identifies initiation point |
Key Finding: When researchers inhibited key steps in the metabolic pathway—using rapamycin to block mTOR, or ascorbate to inhibit HIF-1α—the training effect was abolished 2 .
Studying trained immunity requires specialized tools that target both immune responses and metabolic pathways.
The fungal cell wall component that serves as the classic inducer of trained immunity. It binds to dectin-1 receptors on immune cells, initiating the signaling cascade 2 .
A well-characterized mTOR inhibitor that blocks the metabolic reprogramming essential for trained immunity when added during the initial training phase 2 .
A glucose analog that inhibits glycolysis, allowing researchers to test the metabolic requirements of trained immunity 2 .
An AMPK activator that indirectly inhibits mTOR, helping establish the importance of energy sensing in trained immunity 2 .
A common diabetes drug that activates AMPK and inhibits mTOR, demonstrating how existing medications might modulate trained immunity 3 .
Compounds that prevent HIF-1α accumulation (e.g., ascorbate), testing its essential role in the glycolytic switch 2 .
Understanding the metabolic basis of trained immunity opens exciting therapeutic possibilities. By tweaking the mTOR/HIF-1α/glycolysis axis, we might potentially:
Therapeutic Potential
How trained immunity operates in different tissue environments 3
How central trained immunity in bone marrow stem cells provides sustained protection 3
Evidence suggests trained immunity traits might be transmitted through generations 3
Whether different inducers utilize distinct metabolic pathways
The discovery that mTOR- and HIF-1α-mediated aerobic glycolysis underlies trained immunity represents more than just a mechanistic insight—it fundamentally changes how we view the interplay between metabolism and immunity.
The artificial boundaries we draw between different cellular processes—metabolism, epigenetics, immune function—often obscure their fundamental unity.
The trained immunity story beautifully illustrates how evolution repurposes core metabolic pathways to create sophisticated biological capabilities.
The age of metabolic immunology has arrived, and it promises to rewrite textbooks for generations to come.