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This report is written by MaltSci based on the latest literature and research findings

How does immunometabolism regulate immune responses? ​

Abstract ​

Immunometabolism is an emerging field that investigates the complex relationship between metabolic processes and immune system function. Recent advancements have shown that metabolic pathways play a crucial role in regulating immune responses, with immune cells undergoing metabolic reprogramming to fulfill their roles in both innate and adaptive immunity. This review synthesizes current knowledge on how different metabolic pathways, including glycolysis, oxidative phosphorylation, and fatty acid metabolism, influence immune cell function and behavior. Glycolysis is essential for the activation of effector T cells and macrophages, providing the energy needed for rapid immune responses. Oxidative phosphorylation supports the long-term survival and functionality of these cells, while fatty acid metabolism is pivotal for T cell differentiation and macrophage polarization. Furthermore, specific metabolic intermediates have emerged as important signaling molecules that modulate immune responses, offering potential therapeutic implications for immune-related diseases. The findings presented highlight the significance of understanding immunometabolism in developing novel therapeutic strategies aimed at restoring immune balance and enhancing clinical outcomes in various conditions, including cancer, autoimmune disorders, and infections.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 The Role of Metabolism in Immune Cell Function
    • 2.1 Metabolic Pathways in Innate Immunity
    • 2.2 Metabolic Pathways in Adaptive Immunity
  • 3 Glycolysis and Immune Activation
    • 3.1 Glycolytic Pathway in Macrophages
    • 3.2 Glycolytic Pathway in T Cells
  • 4 Oxidative Phosphorylation and Immune Regulation
    • 4.1 Mitochondrial Function in Immune Cells
    • 4.2 Impact of Oxidative Stress on Immune Responses
  • 5 Fatty Acid Metabolism and Immune Responses
    • 5.1 Role of Fatty Acids in T Cell Differentiation
    • 5.2 Influence of Lipid Metabolism on Macrophage Polarization
  • 6 Metabolic Intermediates as Signaling Molecules
    • 6.1 The Role of Metabolites in Immune Signaling
    • 6.2 Therapeutic Implications of Targeting Metabolic Pathways
  • 7 Conclusion

1 Introduction ​

Immunometabolism is an emerging field that examines the intricate relationship between metabolic processes and immune system function. The interplay between metabolism and immunity has garnered increasing attention over the past decade, as it has become clear that metabolic pathways are crucial in regulating immune responses. Immune cells are not merely passive responders to pathogens; they actively undergo metabolic reprogramming to fulfill their roles in both innate and adaptive immunity. This metabolic reprogramming influences various aspects of immune cell function, including activation, differentiation, and effector responses, thereby impacting overall immune homeostasis and disease progression [1][2].

The significance of immunometabolism extends beyond basic immunological understanding; it holds profound implications for therapeutic interventions in a range of immune-related diseases, including cancer, autoimmune disorders, and infectious diseases. As metabolic dysregulation is often implicated in the pathogenesis of these conditions, targeting metabolic pathways presents a promising avenue for novel therapeutic strategies. Recent studies have highlighted how specific metabolic intermediates and signaling molecules can modulate immune responses, providing new insights into potential treatment modalities [3][4]. Understanding the mechanisms underlying immunometabolism is thus essential for developing effective interventions that can restore immune balance and improve clinical outcomes.

Current research in immunometabolism has revealed a variety of metabolic pathways that play critical roles in immune cell function. Glycolysis, oxidative phosphorylation, and fatty acid metabolism are among the key pathways that influence immune cell activation and differentiation. For instance, glycolysis is essential for the rapid energy demands of activated immune cells, while oxidative phosphorylation contributes to long-term survival and function. Furthermore, fatty acid metabolism is crucial for the differentiation of specific immune cell subsets, such as T cells and macrophages [5][6]. These metabolic pathways are not isolated; they interact with various signaling networks that dictate immune cell fate and function [7][8].

The present review will synthesize the current knowledge on how different metabolic pathways regulate immune responses, organized as follows:

  1. The Role of Metabolism in Immune Cell Function: This section will explore the distinct metabolic pathways in innate and adaptive immunity, detailing how these pathways influence immune cell behavior and functionality.

  2. Glycolysis and Immune Activation: A focused discussion on the role of glycolysis in macrophages and T cells will be presented, emphasizing how this pathway supports immune activation.

  3. Oxidative Phosphorylation and Immune Regulation: This section will examine mitochondrial function in immune cells and the impact of oxidative stress on immune responses.

  4. Fatty Acid Metabolism and Immune Responses: Here, we will discuss the role of fatty acids in T cell differentiation and the influence of lipid metabolism on macrophage polarization.

  5. Metabolic Intermediates as Signaling Molecules: This part will highlight how various metabolites act as signaling molecules that modulate immune responses, along with their therapeutic implications.

  6. Conclusion: The review will conclude with a summary of the key findings and potential future directions in the field of immunometabolism.

By elucidating the connection between immunometabolism and immune responses, this review aims to provide a comprehensive overview of how metabolic reprogramming can be leveraged to enhance or suppress immune functions, ultimately contributing to better clinical outcomes. The insights gained from this exploration will not only deepen our understanding of immune regulation but also pave the way for innovative therapeutic strategies targeting metabolic pathways in immune-related diseases [9][10].

2 The Role of Metabolism in Immune Cell Function ​

2.1 Metabolic Pathways in Innate Immunity ​

Immunometabolism, the study of how metabolic processes influence immune cell function, plays a critical role in regulating immune responses. The interaction between metabolism and immune cell function is vital for maintaining homeostasis and responding effectively to various stimuli, including infections and autoimmune conditions.

Metabolism in immune cells is primarily driven by several key pathways, including glycolysis, oxidative phosphorylation (OXPHOS), and fatty acid oxidation. These pathways not only provide the necessary energy for immune cell survival and activity but also produce metabolites that serve as signaling molecules, influencing immune responses. For instance, during immune activation, effector T cells exhibit increased glycolysis to meet the heightened energy demands associated with proliferation and function, a process termed metabolic reprogramming. This metabolic shift is crucial for the effective activation of immune responses, particularly in conditions like autoimmune diseases where the immune system can become dysregulated [2][8].

Innate immune cells, such as macrophages and dendritic cells, also undergo metabolic changes that are essential for their function. These cells adapt their metabolism in response to environmental cues, which is critical for their roles in pathogen recognition and response. For example, macrophages can switch between pro-inflammatory and anti-inflammatory states based on their metabolic state, influenced by the availability of nutrients and the presence of pathogens. This metabolic flexibility allows them to efficiently respond to different immunological challenges [11][12].

Moreover, specific metabolites produced during metabolic processes have been identified as key regulators of immune responses. For instance, itaconate, derived from the TCA cycle in activated macrophages, has been shown to inhibit the NLRP3 inflammasome and reduce the production of pro-inflammatory cytokines, thereby modulating inflammation. This highlights how metabolites can directly influence immune cell behavior and contribute to the regulation of immune responses [3].

The intricate interplay between metabolism and immune cell function also extends to the regulation of immune tolerance. Regulatory T cells (Tregs), which are essential for maintaining immune homeostasis, rely on specific metabolic pathways to exert their suppressive functions. The integration of metabolic cues with their transcriptional and signaling networks is crucial for Treg differentiation and function, demonstrating the importance of metabolic regulation in immune tolerance and the prevention of autoimmune diseases [8].

In summary, immunometabolism is a vital component of immune regulation, influencing how immune cells respond to environmental changes and pathogen challenges. The dynamic interplay between metabolic pathways and immune functions underpins the ability of the immune system to maintain homeostasis and respond appropriately to threats, thereby providing insights into potential therapeutic strategies for managing autoimmune diseases and enhancing immune responses in various contexts [1][5].

2.2 Metabolic Pathways in Adaptive Immunity ​

Immunometabolism is a crucial concept that underscores the interplay between metabolic processes and immune responses, significantly influencing immune cell function and differentiation. The regulation of immune responses through immunometabolism involves various metabolic pathways that are essential for the activation, proliferation, and function of immune cells.

During immune responses, immune cells undergo metabolic reprogramming to meet the energy demands required for their activities. This reprogramming is particularly evident in adaptive immunity, where effector T cells exhibit increased glycolysis to support their proliferation and function during immune responses. For instance, effector T cells rely on enhanced glycolytic pathways to generate ATP and metabolic intermediates necessary for cell growth and differentiation, thereby directly linking metabolism to immune functionality [3].

Furthermore, specific metabolites generated during these metabolic processes act as signaling molecules that modulate immune activity. For example, itaconate, produced from the tricarboxylic acid (TCA) cycle by the enzyme aconitate decarboxylase 1 (ACOD1), plays a significant role in regulating inflammation. Itaconate has been shown to inhibit the NLRP3 inflammasome and reduce the production of pro-inflammatory cytokines such as IL-1β and IL-6, thereby impacting the immune response [3]. This indicates that metabolic by-products not only provide energy but also serve as critical regulators of immune signaling pathways.

In addition to glycolysis, other metabolic pathways, including fatty acid oxidation and amino acid metabolism, also contribute to the modulation of immune responses. Alterations in these pathways can lead to changes in immune cell behavior, influencing the progression of autoimmune diseases. For instance, in the context of immune thrombocytopenia (ITP), metabolic dysfunctions have been linked to abnormal activation and differentiation of immune cells, which subsequently leads to attacks on self-tissues [2].

The concept of immunometabolism extends beyond mere energy production; it encompasses a complex network of signaling pathways that influence the differentiation of various immune cell types. Immune cells, such as macrophages and T cells, adapt their metabolic programs according to their microenvironment, which is critical for maintaining homeostasis and responding effectively to pathogens [1]. The metabolic state of these cells can determine their fate, influencing whether they adopt pro-inflammatory or anti-inflammatory roles.

Moreover, the impact of nutrition on immunometabolism cannot be overlooked. The composition of dietary components, including proteins, lipids, and carbohydrates, shapes the metabolic pathways utilized by immune cells, particularly in the gut, where the immune system first encounters food antigens [13]. This dietary influence highlights the significance of lifestyle factors in modulating immune responses through metabolic mechanisms.

In summary, immunometabolism plays a pivotal role in regulating immune responses by linking metabolic pathways to immune cell function. The metabolic reprogramming of immune cells is essential for their activation, differentiation, and overall function, with specific metabolites serving as key modulators of immune activity. Understanding these mechanisms provides insights into potential therapeutic strategies for various diseases, including autoimmune disorders and infections [5][14].

3 Glycolysis and Immune Activation ​

3.1 Glycolytic Pathway in Macrophages ​

Immunometabolism plays a critical role in regulating immune responses, particularly through the modulation of metabolic pathways in immune cells such as macrophages. Macrophages, as essential innate immune cells, exhibit metabolic flexibility that allows them to adapt their energy production to meet the demands of various immune functions, including inflammation and tissue repair.

One of the most significant metabolic pathways involved in macrophage activation is glycolysis. During inflammatory responses, macrophages typically undergo a metabolic shift towards glycolysis, which enables rapid ATP production necessary for their effector functions. This glycolytic activation not only provides energy but also generates metabolic intermediates that are crucial for sustaining pro-inflammatory responses. For instance, glycolysis is associated with the production of lactate, which can influence the cellular redox state and serve as a signaling molecule that promotes inflammation [15].

Macrophages can adopt different phenotypes based on their metabolic state. Classically activated or M1 macrophages primarily rely on glycolysis for energy, allowing them to produce pro-inflammatory cytokines and effectively respond to pathogens. In contrast, alternatively activated or M2 macrophages utilize oxidative phosphorylation and fatty acid oxidation, which are essential for resolving inflammation and promoting tissue repair [16][17]. This metabolic dichotomy illustrates the interplay between metabolism and macrophage function, as the choice of metabolic pathway directly influences the inflammatory phenotype of these cells.

Recent studies have emphasized the role of specific metabolic pathways in shaping macrophage responses. For example, the pentose phosphate pathway (PPP) has been shown to be crucial for generating NADPH, which is vital for maintaining the oxidative burst in M1 macrophages [18]. Furthermore, the activation of the tricarboxylic acid (TCA) cycle is essential for providing substrates that support both energy production and the biosynthesis of inflammatory mediators [19].

Moreover, the regulation of glycolytic metabolism in macrophages is not merely a passive response to environmental stimuli; it is a dynamic process influenced by various factors, including cytokines and pathogen-associated molecular patterns (PAMPs) [20]. For instance, lipopolysaccharide (LPS) stimulation has been shown to significantly upregulate glycolytic enzymes and enhance glycolytic flux in macrophages, facilitating their inflammatory response [21].

The manipulation of metabolic pathways in macrophages presents a potential therapeutic strategy for modulating immune responses. Targeting glycolysis and associated metabolic intermediates could influence macrophage polarization and activity, thereby providing a means to either enhance anti-inflammatory responses or suppress excessive inflammation [22]. Understanding the intricate relationship between macrophage immunometabolism and immune activation is paramount for developing novel approaches to treat inflammatory diseases and improve outcomes in various clinical settings.

In summary, the regulation of immune responses through immunometabolism, particularly via glycolysis in macrophages, underscores the complexity of immune cell activation and highlights the potential for metabolic interventions in therapeutic applications.

3.2 Glycolytic Pathway in T Cells ​

Immunometabolism plays a critical role in regulating immune responses, particularly through the modulation of glycolysis in T cells. T cells, which are essential components of the adaptive immune system, undergo significant metabolic reprogramming during activation, primarily shifting their energy production from oxidative phosphorylation to glycolysis. This shift is vital for meeting the energy demands associated with T cell proliferation and effector functions.

During immune activation, effector T cells, including CD8+ T cells, primarily rely on glycolysis to support their rapid expansion and function. This metabolic pathway provides not only ATP but also intermediates that are crucial for biosynthetic processes required for cell growth and proliferation. The activation of T cells triggers an increase in glycolytic enzymes, which enhances the glycolytic flux, thus ensuring that these cells can efficiently respond to antigens and proliferate in response to immune challenges[3].

In contrast, regulatory T cells (Tregs) predominantly utilize oxidative phosphorylation and fatty acid oxidation for their energy needs. This metabolic distinction highlights the functional diversity of T cell subsets, where glycolysis supports the pro-inflammatory functions of effector T cells, while Tregs maintain immune homeostasis and suppress excessive immune responses[23].

Furthermore, glycolytic metabolites can act as signaling molecules that directly influence T cell function. For instance, itaconate, a metabolite derived from the tricarboxylic acid (TCA) cycle, has been shown to modulate immune responses by inhibiting pro-inflammatory cytokines and promoting Treg differentiation. Itaconate's ability to suppress Th17 differentiation while enhancing Foxp3 expression in Tregs exemplifies how metabolic intermediates can shape immune cell fate and function[3].

The regulation of glycolysis in T cells is also linked to critical signaling pathways, such as the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Activation of mTORC1 is necessary for promoting glycolysis, and this pathway is responsive to nutrient availability, particularly glucose and amino acids. Glutamine, for example, serves as a key metabolite that supports T cell activation by enhancing glycolytic activity and mTORC1 signaling[24].

In summary, immunometabolism, particularly through the glycolytic pathway, is integral to T cell activation and function. The metabolic reprogramming that occurs during T cell activation not only provides the necessary energy and building blocks for proliferation but also influences the differentiation and functional outcomes of various T cell subsets. Understanding these metabolic pathways opens new avenues for therapeutic interventions in immune-related diseases, including cancer and autoimmune disorders[25].

4 Oxidative Phosphorylation and Immune Regulation ​

4.1 Mitochondrial Function in Immune Cells ​

Immunometabolism is a crucial field that explores the intersection of metabolic processes and immune responses, particularly focusing on how metabolic pathways influence the activation, differentiation, and function of immune cells. A significant aspect of immunometabolism is the role of oxidative phosphorylation (OXPHOS) and mitochondrial function in regulating immune responses.

Mitochondria serve as central hubs for energy metabolism and are pivotal in modulating immune cell functions. The interplay between mitochondrial metabolism and immune responses is complex and context-dependent. For instance, during immune activation, effector T cells undergo metabolic reprogramming characterized by increased glycolysis and altered OXPHOS, enabling them to meet the heightened energy demands for proliferation and function. This metabolic shift is critical for T cell differentiation, where specific pathways, including glucose, lipid, and amino acid metabolism, are finely tuned to support various immune functions [26].

In macrophages, the metabolic state can determine their polarization into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes. M1 macrophages exhibit disrupted OXPHOS and a broken TCA cycle, leading to an accumulation of metabolites such as succinate, which can further modulate immune responses [27]. Conversely, M2 macrophages maintain intact OXPHOS and utilize fatty acid oxidation, contributing to their anti-inflammatory roles [28]. The metabolic environment, therefore, plays a critical role in dictating the functional outcomes of macrophages in inflammatory contexts.

Mitochondrial dysfunction can also have broader implications for immune regulation. In mitochondrial diseases, bioenergetic deficiencies not only impact metabolic pathways but also alter immune system functionality, leading to immune dysregulation [29]. This highlights the interconnectedness of metabolic health and immune competence.

Furthermore, specific metabolites generated through mitochondrial pathways, termed immunometabolites, can directly influence immune responses. For example, itaconate, produced from the TCA cycle, has been shown to inhibit pro-inflammatory cytokines and modulate T cell metabolism, enhancing regulatory T cell functions while suppressing Th17 differentiation [3]. Such findings emphasize the role of mitochondrial-derived signals in shaping immune responses.

The relationship between OXPHOS and immune regulation extends to innate immunity as well. Mitochondrial metabolism is essential for the proper functioning of innate immune cells, including the activation of pathways such as the retinoic acid-inducible gene I (RLR) signaling, which is critical for antiviral responses [30]. Impairments in mitochondrial function can lead to reduced immune surveillance and increased susceptibility to infections [30].

In summary, immunometabolism, particularly through the lens of oxidative phosphorylation and mitochondrial function, plays a fundamental role in regulating immune responses. The metabolic adaptations of immune cells, dictated by mitochondrial activity, not only influence their activation and differentiation but also their overall capacity to respond to pathogenic challenges. Understanding these intricate relationships offers potential therapeutic avenues for targeting metabolic pathways to modulate immune responses in various diseases, including autoimmune conditions and cancer.

4.2 Impact of Oxidative Stress on Immune Responses ​

Immunometabolism is a critical field that explores the intersection of metabolic processes within immune cells and their functional outcomes, particularly in the context of immune responses. One of the central components of immunometabolism is oxidative phosphorylation (OXPHOS), which plays a pivotal role in modulating immune cell activity and function.

OXPHOS is responsible for producing adenosine triphosphate (ATP) through the electron transport chain, which is essential for energy supply in immune cells. The regulation of OXPHOS can significantly influence immune responses. For instance, in the context of cancer, alterations in OXPHOS not only provide sufficient energy for tumor survival but also regulate the tumor microenvironment, affecting immune cell functions and leading to immune evasion. Studies have shown that metabolic shifts towards enhanced OXPHOS can contribute to tumor proliferation and metastasis, thereby impairing the immune function of surrounding immune cells[31].

Moreover, the interplay between oxidative stress and immune responses is crucial. Oxidative stress arises from an imbalance between pro-oxidants and antioxidants, and it is implicated in the pathogenesis of various diseases, including cancer and autoimmune disorders. This stress can affect immune cell function by altering metabolic pathways and impacting the survival and activation of immune cells. For example, chronic nitro-oxidative stress can inhibit the activity of antioxidant systems and disrupt mitochondrial functions, which are vital for the metabolic reprogramming of immune cells. This disruption can lead to impaired phagocytosis, altered cytokine production, and changes in immune cell polarization[32].

Additionally, the role of specific metabolites generated during metabolic processes has been highlighted in regulating immune activity. For instance, itaconate, derived from the tricarboxylic acid (TCA) cycle, has been shown to inhibit pro-inflammatory cytokines and modulate immune responses by affecting T cell metabolism and differentiation. This suggests that metabolites not only serve as energy sources but also act as signaling molecules that can directly influence immune functions[3].

The modulation of immune responses through immunometabolism is particularly relevant in the context of inflammation and autoimmunity. Immune cells, such as T cells and macrophages, undergo metabolic reprogramming during activation, which involves a shift towards glycolysis and enhanced OXPHOS to meet the energetic demands of proliferation and function. This metabolic reprogramming is essential for effective immune responses, particularly in autoimmune diseases where dysregulated immune activity can lead to tissue damage and chronic inflammation[33].

In conclusion, immunometabolism, through the regulation of oxidative phosphorylation and the impact of oxidative stress, plays a fundamental role in shaping immune responses. The intricate balance of metabolic pathways not only dictates energy availability but also influences the activation, differentiation, and function of various immune cell types. Understanding these mechanisms offers potential therapeutic avenues for modulating immune responses in various pathological conditions, including cancer and autoimmune diseases.

5 Fatty Acid Metabolism and Immune Responses ​

5.1 Role of Fatty Acids in T Cell Differentiation ​

Immunometabolism, the intersection of immune function and cellular metabolism, plays a crucial role in regulating immune responses, particularly through the modulation of fatty acid metabolism in T cells. Fatty acids serve not only as energy substrates but also as critical regulators of T cell differentiation and function. The metabolic state of T cells influences their activation, proliferation, and fate decisions, which are essential for effective immune responses.

The differentiation of T cells into various subsets, such as effector T cells and regulatory T cells (Tregs), is closely linked to their metabolic programming. For instance, effector T cells predominantly rely on glycolysis and glutamine oxidation to meet their bioenergetic demands during activation and proliferation. In contrast, Tregs primarily utilize fatty acid oxidation, highlighting a metabolic dichotomy that underpins the functional diversity of T cell subsets (Tanimine et al., 2018; Endo et al., 2022).

Recent studies have elucidated the significance of fatty acid metabolism in T cell biology. The induction of de novo fatty acid biosynthesis is essential for the proliferation and differentiation of effector T cells upon antigen stimulation. Conversely, fatty acid catabolism via β-oxidation is critical for the generation of memory T cells and the differentiation of Tregs (Endo et al., 2022; Lochner et al., 2015). This metabolic flexibility allows T cells to adapt their functions in response to varying environmental cues, thereby influencing the overall immune response.

Moreover, the presence of free fatty acids and their oxidative derivatives can modulate T cell functions. Unsaturated fatty acids, for example, can be oxidized to generate pro-inflammatory or pro-resolving lipid mediators, which can impact T cell activation and proliferation. This underscores the delicate balance between beneficial and detrimental effects of fatty acids on immune responses (de Jong et al., 2014; Hu et al., 2018).

In pathological contexts, such as obesity, the dysregulation of fatty acid metabolism can lead to altered T cell functions and contribute to inflammatory diseases. The excess of certain fatty acids may induce lipotoxicity, impairing T cell activation and leading to dysfunctional immune responses (Böttcher-Loschinski et al., 2022). Understanding these metabolic pathways offers potential therapeutic avenues for modulating immune responses in various diseases, including autoimmune disorders and cancer.

In summary, fatty acid metabolism is a pivotal component of immunometabolism that regulates T cell differentiation and function. The metabolic programming of T cells dictates their fate and capabilities, thereby shaping the immune response. As research progresses, targeting metabolic pathways may provide novel strategies for enhancing immune function or restoring balance in dysregulated immune states.

5.2 Influence of Lipid Metabolism on Macrophage Polarization ​

Immunometabolism plays a critical role in regulating immune responses, particularly through the influence of lipid metabolism on macrophage polarization. Macrophages, as key innate immune cells, exhibit remarkable plasticity, allowing them to adapt their functions based on environmental cues. This adaptability is heavily influenced by their metabolic state, which can be modulated by lipid metabolism.

Lipid metabolism is integral to the polarization of macrophages into two main phenotypes: pro-inflammatory (M1) and anti-inflammatory (M2). M1 macrophages are typically associated with inflammatory responses and rely on glycolysis and lipogenesis for energy and function. They utilize lipids to accumulate energy reserves and support phagocytosis. Conversely, M2 macrophages are characterized by their anti-inflammatory properties and predominantly utilize fatty acid β-oxidation as their primary energy source. This metabolic shift allows M2 macrophages to perform functions such as tissue repair and resolution of inflammation [34].

The regulation of lipid metabolism in macrophages is complex and involves various signaling pathways. For instance, the transcription factors SREBPs (Sterol Regulatory Element-Binding Proteins), PPARs (Peroxisome Proliferator-Activated Receptors), and LXRs (Liver X Receptors) are crucial for cholesterol metabolism and the efflux capacity of macrophages. Dysregulation of these pathways can lead to the formation of foam cells, which are associated with increased inflammatory cytokine production and are implicated in conditions such as atherosclerosis [34].

Furthermore, the manipulation of metabolic intermediates and enzymes linked to lipid metabolism can significantly influence macrophage reprogramming. This, in turn, affects the generation of either pro-inflammatory or anti-inflammatory responses. For example, enhancing fatty acid oxidation has been shown to promote the M2 phenotype, which is beneficial in the context of resolving inflammation and promoting tissue repair [35].

The interplay between lipid metabolism and macrophage polarization is also evident in the context of diseases such as obesity and type 2 diabetes, where altered lipid metabolism contributes to chronic inflammation and immune dysfunction. In these conditions, the metabolic reprogramming of macrophages leads to a predominance of M1 macrophages, exacerbating inflammatory responses [36].

In summary, lipid metabolism is a fundamental aspect of immunometabolism that critically influences macrophage polarization and function. By understanding these metabolic pathways, it may be possible to develop targeted therapeutic strategies aimed at modulating macrophage activity in various inflammatory and metabolic diseases, thereby restoring immune homeostasis and improving disease outcomes [37][38].

6 Metabolic Intermediates as Signaling Molecules ​

6.1 The Role of Metabolites in Immune Signaling ​

Immunometabolism plays a critical role in regulating immune responses through the modulation of metabolic pathways within immune cells. The concept of immunometabolism encompasses the metabolic reprogramming that occurs during immune activation, which is crucial for the homeostasis, activation, proliferation, and differentiation of various immune cell subsets. Metabolic intermediates generated during these processes not only serve as energy sources but also function as signaling molecules that influence immune activity.

Recent studies have highlighted the significance of metabolites such as lactate, succinate, itaconate, and fumarate in immune signaling. For instance, lactate, traditionally viewed as a waste product of anaerobic glycolysis, has emerged as a pivotal regulator of immune responses. It influences immune cell polarization, differentiation, and effector functions, demonstrating its role beyond mere metabolic byproduct [39]. Additionally, lactate acts as a signaling molecule by modulating various immune pathways, including the regulation of cytokine production and the activation of transcription factors [40].

Itaconate, derived from the tricarboxylic acid (TCA) cycle, has garnered attention for its ability to regulate macrophage activity and modulate inflammatory responses. Itaconate inhibits the NLRP3 inflammasome and pro-inflammatory cytokines, such as IL-1β and IL-6, thereby exerting anti-inflammatory effects [3]. Furthermore, itaconate influences the metabolism and epigenetics of T cells, enhancing regulatory T cell (Treg) function while suppressing Th17 differentiation [41].

Succinate, another metabolite linked to the TCA cycle, has been shown to act as a signaling molecule that activates the hypoxia-inducible factor (HIF) pathway, leading to enhanced inflammatory responses in macrophages [42]. This highlights the intricate relationship between metabolic intermediates and immune signaling pathways, where metabolites not only provide energy but also actively participate in shaping immune responses.

Moreover, the interaction between metabolites and specific metabolite sensors within immune cells underscores the complexity of immunometabolism. For example, lactate can modify proteins through lactylation, affecting their function and influencing immune activation [40]. Such modifications are critical for balancing inflammation and immune tolerance, suggesting that targeting these metabolic pathways could offer novel therapeutic strategies for immune-mediated diseases.

In summary, immunometabolism is integral to the regulation of immune responses, with metabolic intermediates serving dual roles as energy sources and signaling molecules. This dynamic interplay not only influences immune cell function but also offers potential avenues for therapeutic intervention in various diseases, including autoimmune disorders, infections, and cancer [1][43][44].

6.2 Therapeutic Implications of Targeting Metabolic Pathways ​

Immunometabolism is a rapidly evolving field that examines the intricate relationship between metabolic pathways and immune responses. It highlights how immune cells adapt their metabolism to fulfill their functional roles in both health and disease, thereby influencing the overall immune response. The regulation of immune responses through immunometabolism involves several mechanisms, particularly the role of metabolic intermediates as signaling molecules and the therapeutic implications of targeting these metabolic pathways.

Immune cells rely on specific metabolic pathways to perform their functions effectively. For instance, the metabolic state of immune cells, such as T cells and macrophages, significantly affects their activation, differentiation, and effector functions. During immune activation, these cells undergo metabolic reprogramming to meet the increased energy and biosynthetic demands required for their activities. This metabolic shift is crucial for their ability to produce pro-inflammatory cytokines and execute immune responses effectively. Metabolic intermediates, such as lactate, succinate, and itaconate, serve not only as energy sources but also as signaling molecules that can modulate immune cell behavior. For example, itaconate has been shown to possess anti-inflammatory properties and can influence macrophage polarization, shifting them towards an anti-inflammatory phenotype, thereby impacting the immune response in inflammatory diseases [45].

The therapeutic implications of targeting metabolic pathways in immunometabolism are profound. By manipulating the metabolic pathways of immune cells, it is possible to alter their functional outcomes. This strategy holds potential for treating various diseases, including autoimmune disorders, cancers, and metabolic diseases. Recent studies suggest that pharmacological agents, such as Metformin and DMF, can modify immune cell metabolism and exert anti-inflammatory effects, thus providing new avenues for therapeutic intervention [46]. Additionally, targeting specific metabolic events has emerged as a promising strategy to enhance the efficacy of immunotherapies, particularly in cancer treatment, where metabolic reprogramming of immune cells within the tumor microenvironment can improve antitumor responses [47].

Furthermore, the exploration of metabolic reprogramming in immune cells has identified novel biomarkers and therapeutic targets that can be leveraged to develop personalized medicine approaches. By understanding how metabolic pathways influence immune cell functions, researchers can design targeted therapies that either enhance or suppress immune responses based on the disease context [5]. For instance, in the context of autoimmune diseases, fine-tuning the metabolic pathways of specific immune cell subsets could help restore immune balance and mitigate disease progression [48].

In summary, immunometabolism plays a crucial role in regulating immune responses by linking metabolic pathways to immune cell function. Metabolic intermediates act as signaling molecules that can influence the behavior of immune cells, and targeting these metabolic pathways presents a promising therapeutic strategy for a variety of diseases. As research in this field progresses, it is expected that new therapeutic interventions will emerge, enhancing our ability to modulate immune responses effectively.

7 Conclusion ​

The exploration of immunometabolism has revealed significant insights into how metabolic pathways govern immune responses, highlighting the dynamic interplay between metabolism and immune cell function. Key findings underscore the importance of glycolysis, oxidative phosphorylation, and fatty acid metabolism in regulating the activation, differentiation, and overall functionality of immune cells. Glycolysis is essential for the rapid energy demands of activated immune cells, particularly in T cells and macrophages, while oxidative phosphorylation supports long-term survival and function. Fatty acid metabolism plays a critical role in T cell differentiation and macrophage polarization, demonstrating how metabolic states influence immune responses. Moreover, metabolic intermediates such as itaconate and lactate serve as crucial signaling molecules that modulate immune activity, opening avenues for therapeutic interventions in autoimmune diseases, cancer, and infectious diseases. Future research should focus on elucidating the intricate mechanisms of metabolic regulation in immune cells, exploring how dietary and environmental factors influence immunometabolism, and developing targeted therapies that can effectively modulate immune responses through metabolic pathways. This understanding could lead to innovative treatment strategies aimed at restoring immune balance and improving clinical outcomes across various immune-related conditions.

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