Immunometabolism, a rapidly evolving field at the intersection of immunology and metabolism, has garnered significant attention, particularly amidst the global surge in obesity. This metabolic disorder significantly impacts the immune system, triggering inflammation and contributing to various chronic diseases. Understanding the intricate interplay between metabolism and immunity is crucial for immunologists.
Metabolism Concept
Image Credit: Metabolism involves a complex network of biochemical reactions essential for energy production and cellular function, influencing immune responses.
The Intricate Relationship Between Metabolism and Immunity
The connection between metabolism and immunity is fundamental to multicellular organisms. Efficient nutrient distribution and protection against harmful invaders are both crucial for survival. This necessitates a coordinated interaction between metabolic pathways and immune responses.
Metabolites and metabolic pathway activation play key roles in energy production, intracellular signaling, macromolecule synthesis, post-translational modifications, and cell survival. Inflammation, a key immune response, is also linked to many pathologies associated with metabolic syndrome. Conversely, malnutrition, a metabolic deficiency, can lead to immune suppression.
In a landmark 1993 study, Hotamisligil et al. discovered that adipose tissue produces tumor necrosis factor-alpha (TNFα) in murine models of obesity and diabetes. This groundbreaking research revealed that over-nutrition can induce inflammation, contributing to insulin resistance and ultimately leading to chronic conditions such as diabetes and metabolic syndrome. These findings highlighted the significant impact of metabolic dysregulation on immune function.
Both the metabolism of immune cells and the metabolic regulation of immune cells by metabolic tissues are highly organized processes. Aerobic glycolysis, observed in cancer cells and activated immune cells, is often triggered by oncogenic signaling pathways. Moreover, macrophage metabolism, through specific metabolic programs, can stimulate the synthesis of inflammatory cytokines.
Immunometabolism: A Detailed Overview
Immunometabolism explores the dynamic changes occurring within intracellular metabolic pathways of immune cells following stimulation. This field has identified several key metabolic pathways involved in immune cell function, including:
- Glycolysis: The breakdown of glucose for energy.
- Pentose Phosphate Pathway (PPP): A metabolic pathway parallel to glycolysis that produces NADPH and pentoses, essential for biosynthesis.
- Fatty Acid Synthesis: The production of fatty acids for cell membrane synthesis and energy storage.
- Tricarboxylic Acid (TCA) Cycle: A series of chemical reactions used by all aerobic organisms to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins.
- Amino Acid Metabolism: The breakdown and synthesis of amino acids, the building blocks of proteins.
- Fatty Acid Oxidation: The breakdown of fatty acids for energy.
Glycolysis and fatty acid synthesis are critical for macrophage activation via lipopolysaccharide (LPS), a component of bacterial cell walls. Conversely, macrophage activation mediated by interleukin-4 (IL-4) relies on metabolic pathways such as oxidative phosphorylation and fatty acid oxidation for energy generation. Effector T cells are highly glycolytic, while memory T cells primarily utilize oxidative metabolism, highlighting the metabolic adaptations of different immune cell subsets.
Image Credit: Metabolic pathways are crucial for immune cell function and can be influenced by various stimuli.
Certain metabolites, such as succinate and citrate, possess functions beyond basic metabolism, playing specific roles in cell activation events. Enzymes like pyruvate kinase isoenzyme M2 (PKM2), enolase, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) are also essential components of immune system function. Small molecules targeting metabolic pathways can effectively modify the phenotype of immune cells, opening avenues for therapeutic interventions.
Metabolic Pathways Regulating Immune Metabolism
The metabolism of cytotoxic T cells is of particular interest due to its potential for therapeutic targeting. Research has focused on the uptake and metabolism of key nutrients, including glutamine, glucose, and fatty acids, while also exploring the influence of other metabolites.
Antigen receptor triggering in T cells, coupled with co-stimulation via Cluster of Differentiation 28 (CD28), leads to increased expression of glucose transporter GLUT1, enhanced glucose uptake, and subsequent glycolysis, thereby promoting mitochondrial metabolism. Conversely, inhibitory CD28 family receptors, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death-1 (PD-1), can inhibit this metabolic transition. The absence of CD28 co-stimulation results in T cell anergy and metabolic suppression.
Effector T cells rely on aerobic glycolysis, while memory T cells depend on mitochondrial metabolism and lipid oxidation, allowing them to rapidly switch back to glycolysis upon re-stimulation through endoplasmic reticulum-mitochondrial interactions. Regulatory T cells (Tregs), unlike effector T cell subsets, do not require GLUT1 or high levels of glutamine uptake via the amino acid transporter ASCT2. Tregs primarily utilize mitochondrial lipid, pyruvate, and lactate oxidation.
Similar to T cells, B cell activation and cytokine stimulation trigger glycolysis. However, flux through the pentose phosphate pathway can suppress B cell function, while mitochondrial activity controls apoptosis. The dynamic microenvironment drives glycolysis and influences B cell proliferation and fate. Understanding the pathways regulating B cell metabolism is critical for differentiating between normal B cell function and B cell transformation in leukemia and lymphoma. B cells require precise metabolic support to facilitate high rates of protein synthesis, although the specific metabolic demands of plasmablasts and long-lived plasma cells remain an area of active investigation.
Innate immune cells also undergo metabolic programming, utilizing metabolic pathways to control cell fate. Mononuclear phagocytes bridge innate and adaptive immunity, with cell metabolism regulating inflammatory responses. Dendritic cells exhibit a brief period of oxidative phosphorylation (OXPHOS) upon lipopolysaccharide (LPS) stimulation, followed by downregulation and a shift towards aerobic glycolysis. Macrophages undergo analogous metabolic reprogramming upon encountering danger signals like LPS.
The Role of Immunometabolism in Disease
Viral infections can significantly alter cholesterol synthesis, impacting immune responses. The lung microenvironment, comprised of barrier cells and immune regulatory mechanisms, maintains homeostasis and protects against pathogens. The influenza virus, for example, can trigger metabolic reprogramming in both immune and epithelial cells.
Influenza-induced metabolic reprogramming in epithelial cells is mediated by activation of the PI3K/mTOR/Akt pathway. Influenza infection also affects immune cell populations such as dendritic cells, natural killer (NK) cells, macrophages, and T cells. For instance, influenza infection causes dendritic cells to undergo hyperglycolysis with relatively low oxygen utilization.
Sources:
- Hotamisligil, G. S., et al. “Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.” Science 259.5091 (1993): 87-91.
Further Reading
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