1. Introduction: How Metabolism Shapes the Immune Response
The immune system is the body’s defense network against infections and harmful stimuli. It consists of two main components:
- Innate immunity: rapid responders such as macrophages, neutrophils, and dendritic cells
- Adaptive immunity: specialized defenders like T and B lymphocytes
Innate immune cells detect pathogens through pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). Once activated, they release signaling molecules such as cytokines, chemokines, and antimicrobial peptides to eliminate threats and activate adaptive immunity.
However, mounting an immune response requires significant energy and metabolic reprogramming. Immune cells are not metabolically static—they adapt their metabolism depending on their activation state. This metabolic flexibility is now recognized as essential for proper immune function.
2. Metabolic Reprogramming in Activated Immune Cells
Under resting conditions, immune cells mainly rely on oxidative phosphorylation for energy production. But when activated (for example, by bacterial components like lipopolysaccharide, LPS), they undergo a metabolic shift:
- Decreased oxidative phosphorylation
- Increased glycolysis and pentose phosphate pathway
This switch, similar to the Warburg effect seen in cancer cells, allows for:
- Rapid ATP production
- Maintenance of cellular energy balance
- Generation of biosynthetic precursors needed for cell growth and cytokine production
A key regulator of this process is HIF-1α (hypoxia-inducible factor 1-alpha), which controls genes involved in metabolism and inflammation. It also influences immune cell differentiation, promoting pro-inflammatory T cell responses.
Importantly, metabolism is not just about energy it also produces signaling molecules. Metabolites such as citrate, NAD⁺, and succinate actively regulate immune responses.
3. Citrate: A Key Driver of Inflammatory Mediators
Citrate, a central metabolite of the tricarboxylic acid (TCA) cycle, plays a major role in inflammation.
When immune cells like macrophages are activated:
- Citrate is transported from mitochondria to the cytosol via the mitochondrial citrate carrier (CIC)
- In the cytosol, citrate is converted into acetyl-CoA and oxaloacetate
These molecules are essential for producing:
- Reactive oxygen species (ROS)
- Nitric oxide (NO)
- Prostaglandins (PGs)
All of these are critical mediators of inflammation and host defense. Increased citrate levels in activated immune cells highlight its role as a metabolic signal driving inflammatory responses.
4. NAD⁺ and Sirtuins: Controlling Inflammation
Another important metabolic regulator is NAD⁺, a molecule involved in cellular energy balance.
NAD⁺ activates a group of enzymes called sirtuins, which regulate inflammation by modifying proteins and gene expression.
Key roles of sirtuins include:
- Suppressing inflammatory transcription factors like NF-κB
- Reducing glycolysis and promoting oxidative metabolism
- Enhancing mitochondrial function and biogenesis
- Promoting autophagy (cellular cleanup of damaged components)
For example, Sirt1:
- Inhibits inflammation by deactivating NF-κB
- Reduces production of inflammatory mediators
- Improves mitochondrial health
However, during inflammation ( after LPS stimulation), NAD⁺ levels often decrease, leading to reduced sirtuin activity and enhanced inflammatory signaling.
5. Succinate: A Central Inflammatory Signal
Among metabolic intermediates, succinate has emerged as a powerful signaling molecule in inflammation.
5.1 Succinate Stabilizes HIF-1α
In activated immune cells, succinate accumulates and:
- Inhibits enzymes (prolyl hydroxylases) that normally degrade HIF-1α
- Leads to stabilization of HIF-1α even in normal oxygen conditions
As a result:
- Pro-inflammatory genes are activated
- Cytokines such as IL-1β are produced
- Glycolysis is enhanced
This makes succinate a direct link between metabolism and inflammation.
5.2 Succinate Signals Through SUCNR1
Succinate also acts outside the cell by binding to its receptor, SUCNR1 (formerly GPR91).
Activation of SUCNR1 leads to:
- Calcium signaling and activation of intracellular pathways
- Increased production of inflammatory mediators
- Enhanced migration of dendritic cells
- Improved antigen presentation and T cell activation
This amplifies the immune response and can contribute to conditions such as:
- Autoimmune diseases
- Transplant rejection
6. Succinylation: A New Layer of Regulation
Succinate accumulation also drives a protein modification called succinylation.
This process:
- Adds a chemical group to lysine residues in proteins
- Alters protein structure and function
- Regulates metabolic enzymes
Succinylation affects key pathways such as:
- Glycolysis
- TCA cycle
- Mitochondrial respiration
The enzyme Sirt5 can reverse this modification (desuccinylation), linking it again to NAD⁺ metabolism.
Overall, succinylation represents a novel mechanism connecting metabolism to immune regulation.
7. How Succinate Accumulates in Immune Cells
Several metabolic pathways contribute to increased succinate levels during inflammation:
- Glutamine metabolism feeding into the TCA cycle
- GABA shunt pathway producing succinate
- Reduced activity of succinate dehydrogenase (SDH)
- Possible involvement of the glyoxylate pathway
Additionally:
- Low oxygen (hypoxia)
- Decreased NAD⁺ levels
- Impaired mitochondrial function
all promote succinate accumulation.
8. Conclusion: Metabolism as a Driver of Inflammation
Metabolites such as succinate, citrate, and NAD⁺ are no longer viewed as simple intermediates of cellular metabolism. Instead, they act as key signaling molecules that regulate immune responses.
Among them, succinate stands out because it:
- Activates inflammatory pathways via HIF-1α
- Signals through its receptor SUCNR1
- Modifies proteins via succinylation
Understanding these mechanisms opens new possibilities for therapy. Targeting metabolic pathways could help:
- Boost immunity (e.g., vaccines)
- Reduce excessive inflammation (e.g., autoimmune diseases)
As research advances, metabolic regulation is becoming a central concept in immunology, offering new strategies for controlling inflammation and disease.