Immunometabolism is the study of how metabolic processes influence immune cell functions and how immune responses, in turn, shape cellular metabolism. This field examines the roles of cytokines and metabolites, which act as signaling molecules and energy sources, respectively. Cytokines can trigger or modulate metabolic pathways in immune cells, affecting their activation, growth, and response capabilities. Similarly, metabolites provide the necessary energy and building blocks that enable immune cells to proliferate, function optimally, and sustain their activity during immune responses. This dynamic interplay is crucial for maintaining health and combating disease. Together, cytokines and metabolites orchestrate a complex network that links metabolic health with immune competence on a systemic and cellular level. This blog discusses how cytokines and metabolites not only influence but also drive immune cell functions, revealing new avenues for therapeutic interventions across a range of diseases.

Cytokines and Metabolites in Immunometabolism

Cytokines and metabolites play essential roles as modulators of immune responses, orchestrating the complex interactions between immune cells and their environment. Cytokines are small proteins secreted by cells, particularly by those of the immune system. They function as critical signaling molecules to mediate and regulate immunity, inflammation, and hematopoiesis—the process of forming blood cell components. Metabolites, on the other hand, are small molecules crucial for metabolic reactions, providing essential energy for cells. Examples of primary metabolites include glucose, fatty acids, and amino acids. Together, both cytokines and metabolites can impact:

• Energy production: Metabolites and cytokines support the energy-intensive processes of immune cells during active responses. For instance, metabolites fuel cellular processes through pathways including glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation, providing the energy required for immune cells to function effectively. Cytokines such as interferon-gamma (IFN-γ) also promote glycolysis, which provides the energy needed for rapid response and proliferation of effector immune cells (Chattopadhyay et al., 2023). Other cytokines including interleukin-10 (IL-10) can induce oxidative phosphorylation, a process that promotes the differentiation of regulatory T cells, which suppresses immune responses (Ouyang and O’Garra, 2019).

• Inflammatory response: Metabolites such as succinate amplify this response by acting as an endogenous danger signal; its accumulation in macrophages during inflammation enhances IL-1β production (Tannahill et al., 2013). Other metabolites including itaconate exert anti-inflammatory effects by inhibiting the production of pro-inflammatory cytokines such as IL-6 and IL-1β (Li et al., 2023). Cytokines including TNF-α, IL-1β, and IL-6 also participate in this response by driving the recruitment and activation of immune cells including macrophages and neutrophils to sites of inflammation, amplifying the immune response. Conversely, anti-inflammatory cytokines such as IL-37 help resolve inflammation by inhibiting pro-inflammatory signals (Allaire et al., 2021). In this way, cytokines facilitate cellular communication, ensuring coordinated immune responses across the body (Cui et al., 2024).

• Nutrient sensing and metabolic adaptation: Metabolites can serve as nutrient signals that regulate mTOR activity and other nutrient-sensing pathways in immune cells. For instance, glutamine, a metabolite linked with mTOR signaling, supports the rapid proliferation of activated lymphocytes and macrophages by fueling the TCA cycle (Bodineau et al., 2021). Cytokines can also impact nutrient uptake and utilization in immune cells. For example, depending on the source of IL-6, it can either promote or reduce adipose tissue macrophage accumulation, supporting an appropriate biological response dependent on physiological context (Han et al., 2020).

By influencing these processes, cytokines and metabolites orchestrate the complex interplay between metabolism and immune function, ensuring an appropriate and efficient immune response. Cytokine release can be monitored directly in cells using Lumit® Cytokine Immunoassays, which use a simple, no-wash workflow and are compatible with high-throughput workflows. Additionally, metabolite levels can be assessed with Promega’s metabolite detection assays, which provide a fast, sensitive method for measuring metabolites from diverse sample types.

Immunometabolism in Disease Contexts

Dysregulation of mechanisms involving cytokines and metabolites plays a pivotal role in the onset and progression of numerous diseases. Elevated or diminished levels of specific cytokines can cause chronic inflammation or immune suppression, contributing to autoimmune disorders, infections, and cancers. Similarly, abnormalities in metabolite concentrations can impair cellular functions, resulting in metabolic disorders such as diabetes, cardiovascular diseases, and neurological conditions. In autoimmune conditions including systemic lupus erythematosus (SLE) and multiple sclerosis (MS), dysregulated cytokine and metabolite profiles promote the activation and persistence of autoreactive immune cells, leading to tissue damage and chronic inflammation (Psarras & Clarke, 2023). Tumor cells in various cancers have also been shown to manipulate cytokines and alter metabolite levels to create an immunosuppressive environment that aids their survival and growth (Cortellino & Longo, 2023). Thus, understanding the intricate relationship between cytokine and metabolite dysregulation and disease mechanisms is essential for developing targeted therapies and improving patient outcomes.

Conclusion

Overall, immunometabolism represents a novel perspective on the intricate relationship between metabolic processes and immune function. By examining the roles of both cytokines and metabolites, this field provides crucial insights into how metabolic and immune systems interact to maintain health and contribute to disease. The dysregulation of these processes can lead to a wide range of pathological conditions, from autoimmune diseases and infections to cancers and metabolic disorders. Therefore, it is crucial to enhance our understanding of the complex interplay between cytokines and metabolites. By leveraging this knowledge, we can develop more precise and effective treatments. As research progresses, the integration of immunometabolism into clinical practice holds the promise of significantly improving patient outcomes and revolutionizing how we approach the treatment of immune and metabolic disorders.

To learn more about metabolic profiling of immune cells, view this poster: Simple cell-based assays for profiling metabolism in cell therapy products. 

Want to quantify cytokines and metabolites in your samples? View our portfolio of Lumit® Cytokine Immunoassays and Energy Metabolism Products.

References

Allaire, J.M. et al. (2021) Interleukin-37 regulates innate immune signaling in human and mouse colonic organoids. Scientific Reports, 11(1), 8206.

Bodineau, C. et al. (2021) Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis. Nature Communications, 12(1), 4814.

Chattopadhyay, A. et al. (2023) IFN-γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapy. Frontiers in Immunology, 14, 1282653.

Cortellino, S. and Longo, V. D. (2023) Metabolites and Immune Response in Tumor Microenvironments. Cancers, 15(15), 3898.

Cui, A. et al. (2024) Dictionary of immune responses to cytokines at single-cell resolution. Nature, 625(7994), 377-384.

Han, M.S. et al. (2020) Regulation of adipose tissue inflammation by interleukin 6. Proc. Natl. Acad. Sci. USA, 117(6), 2751-2760.

Li, Z. et al. (2023) Itaconate: A Potent Macrophage Immunomodulator. Inflammation, 46(4), 1177-1191.

Ouyang, W. and O’Garra, A. (2019) IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation. Immunity, 50(4), 871-891.

Psarras, A. and Clarke, A. (2023) A cellular overview of immunometabolism in systemic lupus erythematosus. Oxford Open Immunology, 4(1), iqad005.

Tannahill, G. M. et al. (2013) Succinate is a danger signal that induces IL-1β via HIF-1α. Nature, 496(7444), 238-242.