Metabolism and immune function -
Metabolism encompasses all chemical processes, from digestion to the movement of chemicals from one cell to another. Human metabolism gets split into two distinct components, catabolism, and anabolism. Which the body meticulously regulates to keep in balance despite its complexity. Catabolism refers to breaking down food substances into simpler forms, such as carbs, proteins, and dietary fats, so your body can use them as fuel and the fundamental building blocks for development and repair.
The portion of metabolism known as anabolism is where your body is built or repaired. The energy needed for anabolism eventually comes from food. When your metabolic systems are working correctly, there is a low chance that you will develop disorders that could harm your overall health. Thus dysfunction and disease can set in.
The need to better understand the complexities of this system grows as the development of immunotherapies to treat metabolic diseases continues. The complex network of metabolism and the immune system is described in this article from the standpoint of nutrition.
The immune system creates white blood cells, other chemicals, and proteins that target and eliminate unwanted pathogens or microbes. The immune system needs an effective metabolism to undertake the difficult work of safeguarding your body.
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Every cell in the body undergoes metabolism, including immune cells. It is because the process of producing immune cells is a metabolic activity. The effectiveness and reliability of metabolic processes determine how their products and byproducts turn out. The immune system and metabolism have a close relationship.
Two of the most fundamental tasks of a cell are to obtain enough nutrients and energy to sustain life and to protect itself from potentially dangerous microorganisms.
In this context, it is unsurprising that the immune system gets intimately linked to metabolic activity. According to a study , energy gets required for the immune response, including producing and preparing white blood cells to fight infections and diseases.
The immune system is one of the most potent bodily defensive mechanisms, armed with a slew of defence cells that can wipe off infections that come into contact with them.
The body also possesses several fail-safe mechanisms to prevent the immune system from attacking itself. However, occasionally these protections fail, and we experience an uncalled-for inflammatory reaction.
Observing an influx of immune cells, such as T-cells and B-cells, moving into organs and tissues is the most straightforward approach to gauge this response. Instead, immune cells speed up their metabolism and take in more nutrients when an attack is imminent to generate the proteins necessary for defence, such as cytokines and antibodies.
The immune system can fool itself into believing it is starving by suppressing an immunological response and shutting down metabolism. Metabolism forms the basis for the production of quality immune cells.
Any alteration in the process can lead to deficits and malfunctioning of immune cells. For example, faulty product manufacturing only necessitates poor functioning and operational adjustments.
Correction or intervention targeting the proper production only gives the best functional output. The same is true for immune cells.
Altered metabolism creating malfunctioned cells can only lead to a disorder. Interventions to correct or smoothen the metabolic processes can produce near desirable results. A crucial part of metabolism is utilising your fuel reserves effectively and converting them into energy to assist your immune system.
Some factors that can enhance metabolic flexibility and are also crucial for a well-built immune system are listed below:. Your immune system needs to rest to be strong and alert.
The immune system and sleep are interrelated and impact one another. Studies show a direct link between sleep deprivation and an increased risk of illness. Due to a reduction in the synthesis of cytokines, which are molecules that make up the immunological response, poor sleep impairs your immune system.
These clocks are updated based on your actions, including how much sunlight you receive, when you eat, and how much you sleep.
The immune system and the patterns of physiological cycles that occur daily in every cell of our body get regulated by biological clocks, which also control metabolism.
The mind and body are intricately linked. Also, stress comes in various forms. However, there is a distinction between acute and chronic stress. These cells identify infected cells and signal or even fight them.
Center: metabolic pathways in T cells are mainly discussed by the reviews from Dr. Cantrell, Dr. Rathmell, and colleagues, while those in innate immunity are from Dr. Bensinger, Dr. Ting, and colleagues.
Left: immunometabolism of B cell biology, dendritic cell biology, and macrophage biology are mainly discussed by the reviews from Drs. Boothby, Ho, and Sancho, respectively.
Right: metabolic network is discussed by the review from Dr. Kuchroo and colleagues, and cell-cell crosstalk and organismal metabolism are discussed by the reviews from Dr. Kallies, Dr. Lynch, and colleagues. Cells in the innate and adaptive immune systems are characterized by rapid transition between the quiescent and activated states, marked heterogeneity of cell fate choices, and context-specific tissue adaptation.
Associated with such temporospatial regulation of immune reactions is the dynamic reprogramming of cell metabolism and the crosstalk with signal transduction, including the signaling roles mediated by metabolites and nutrients. Focusing on T cells, a central cell type in adaptive immunity, the reviews from Dr.
Doreen Cantrell [ 5 ], Dr. Jeffrey Rathmell [ 6 ], and colleagues discuss the intrinsic and extrinsic mechanisms for metabolic controls, respectively. T cell activation is accompanied by a pronounced increase in cell size and induction of activation markers, followed by cell cycle entry, clonal expansion, and lineage differentiation.
More recent studies, however, highlight the massive remodeling of the proteome and metabolome accompanying these events, which is the focus of the review from Marchingo and Cantrell [ 5 ]. The authors discuss the general features of protein synthesis and degradation, their dynamic regulation upon T cell activation and differentiation, and the power of high-resolution mass spectrometry technology for proteomic profiling.
The authors also describe the crosstalk between protein remodeling and energy metabolism including glycolytic and oxidative metabolism, and the roles of Myc and mTORC1 signaling as central nodes in connecting these processes.
Specifically, T cell activation results in a pronounced increase of Myc expression and mTORC1 activation, which in turn drive the transcriptional and translational upregulation of metabolic enzymes, respectively.
Heintzman, Fisher, and Rathmell discuss how T cell responses and functions are shaped by extrinsic signals from the tissue microenvironment, including macronutrients e. The authors also describe the regulation and function of T cell immunity in obesity and cancer, with a particular focus on the tumor microenvironment TME.
Deciphering these processes offers an exciting opportunity to understand tissue immunity and develop innovative strategies for cancer therapy. Of note, these intrinsic and extrinsic processes in T cell responses are intimately linked. For example, both protein synthesis and metabolic reprogramming in T cell activation require active uptake of amino acids, which serve as both building blocks and energy sources [ 5 ].
Equally dynamic is the interplay between immunometabolism and innate immunity, as reviewed by Dr. Steven Bensinger [ 7 ], Dr. Jenny Ting [ 8 ], and colleagues. Analogous to antigen-driven activation of T cells, macrophages profoundly reprogram cellular cholesterol homeostasis upon engagement of pattern recognition receptors PRRs [ 7 ].
Lee and Bensinger first provide the overview of cholesterol metabolism, including its synthesis, import, export, and esterification, followed by the emerging concepts for three separate pools of plasma membrane cholesterol encompassing metabolically active, sphingomyelin-sequestered, and essential pools.
The authors then discuss how cholesterol metabolism in macrophages is reprogrammed by PRRs and proinflammatory stimuli, and how these changes tune the sensitivity to cholesterol-dependent cytolysins, a family of pore-forming toxins that rely on cholesterol for their effector function.
Metabolic coordination of innate immunity therefore serves important roles in infectious and inflammatory diseases. While immune responses and metabolic programs are known to depend upon signals transduced from surface immune receptors, we are just beginning to understand how intracellular innate immune sensors and receptors intersect with metabolic pathways, as reviewed by Chou, Rampanelli, Li and Ting [ 8 ].
The authors discuss how metabolic pathways affect the activities of PRRs including NOD-like receptors NLRs , AIM2-like receptors, and STING signaling, and how these intracellular innate immune receptors impact multiple metabolic pathways. For instance, alterations in glycolytic or tricarboxylic acid cycle TCA intermediates, mitochondrial activity, or systemic metabolism can perturb the metabolic circuits, leading to the accumulation of specific endogenous metabolites or danger molecules that in turn activate the NLR receptor NLRP3 and induce inflammation.
It is important to note that many of the intracellular innate immune receptors can also affect the metabolism and function of T cells and B cells, suggesting their important roles in bridging the innate and adaptive immune systems.
Collectively, these reviews provide new insights into the emerging concept of bidirectional metabolic signaling.
Indeed, while it was relatively well understood that immune signaling drives metabolic activation [ 9 ], more recent studies reveal that metabolites have signaling roles in both the innate and adaptive immune systems [ 3 ]. We also start to unravel the sensing and signaling mechanisms underlying how nutrients license immune cell function and cancer immunity [ 10 , 11 , 12 , 13 ].
With the increasing understanding of metabolic signaling, its impacts on immune cell activation state and fate decision are also recognized.
Since the initial discoveries of metabolic reprogramming of T cell activation [ 9 , 14 ] and differentiation [ 15 , 16 , 17 ], the past few years have witnessed remarkable advances in the knowledge on metabolic coordination of T cell immunity, as discussed above [ 5 , 6 ].
Emerging studies also lead to better understanding of metabolic controls of B cell, DC and macrophage biology, as reviewed by Dr. Mark Boothby [ 18 ], Dr. Ping-Chih Ho [ 19 ], Dr. David Sancho [ 20 ], and colleagues, respectively.
First, Boothby, Brookens, Raybuck, and Cho provide a comprehensive review on immunometabolism of the mature B cell lineage, which culminates in antibody secretion for effective humoral immunity [ 18 ]. The authors describe the interplay between nutrients, metabolic programs, and signaling pathways, and their roles in naïve B cell activation, fate choices between cell death, survival, cycling, and terminal differentiation to form plasma cells, and building and fueling the antibody secretion machinery.
In particular, the review focuses on nutrient supply e. While nutrient use and bidirectional metabolic signaling are conserved between B cells and T cells, B cells also use many unique programs to support their lineage choices and antibody production. Second, Moller, Wang, and Ho review metabolic programming in DCs, the key antigen-presenting cells linking innate and adaptive immunity, in immune responses and homeostasis [ 19 ].
Several metabolic programs are discussed, including glycolysis, mitochondrial metabolism, lipids, and ER homeostasis, as well as their crosstalk with mTORC1, AMPK, and Hippo kinases.
The authors describe these metabolic changes and requirements underlying DC development, activation, maturation, tolerogenic function, and cross-presentation.
In particular, they focus on how metabolism controls DC function in the TME and for the interaction with microbiota, as examples of context-specific metabolic rewiring of DC function. Third, Wculek, Dunphy, Heras-Murillo, Mastrangelo, and Sancho review immunometabolism of tissue macrophages [ 20 ].
As tissue-resident immune cells mediating innate immunity and tissue homeostasis, macrophages execute tissue-specific specialized functions, and accordingly they adapt their metabolism in response to particular microenvironmental cues, such as nutrients, pathogens, and disease states.
The review provides a comprehensive discussion of the diverse metabolic activities and adaptations of macrophages residing in lung, spleen, liver, peritoneum, adipose tissue, brain microglia , and bone osteoclasts , and the impacts of macrophage metabolism on tissue repair and regeneration.
How dysregulation of macrophage metabolism contributes to chronic pathologies such as overnutrition, atherosclerosis, and cancer, and the therapeutic implications, are also reviewed. In summary, these review articles provide cutting-edge information on how immunometabolism drives immune cell state and fate and contributes to immune function and tissue homeostasis.
One main challenge of studying metabolic pathways is their complexity, which stems from the vast number of metabolites, the diverse chemical structures, and the sophisticated regulation of the enzymes that control them.
Similarly, the immune system encompasses heterogeneous cell types, subsets, and activation states, and context-specific interactions with environment and other cells.
Therefore, an integrative view is important to understand metabolic control of cellular, tissue, and organismal homeostasis by deciphering the intracellular metabolic network [ 21 ], cell-cell interaction between immune and metabolic tissues [ 22 ], and the interplay between immune cells and diet [ 23 ], as reviewed by Dr.
Vijay Kuchroo, Dr. Axel Kallies, Dr. Lydia Lynch, and colleagues, respectively. Purohit, Wagner, Yosef, and Kuchroo discuss systems-based approaches to study immunometabolism [ 21 ].
The authors first discuss experimental approaches to measure cellular metabolism, including metabolic flux analysis, flow cytometry, single-cell RNA-sequencing, metabolomics, and CRISPR-based functional genomics screens.
The authors then describe computational approaches and mathematical modeling of cellular metabolism, including both kinetic and steady-state approaches, and the applications of these systems-based approaches to study immunometabolism.
Specifically, these approaches have been applied to advance the understanding of environment-specific metabolic dependencies of immune cells, identification of novel disease regulators, integration of multiomics for network building, and genome-scale metabolic modeling of patient data.
Therefore, systems biology approaches and computational models are powerful tools to interrogate the metabolic network of immune cells and predict disease targets. While investigations of cellular and organismal metabolism have evolved separately in the space of immunometabolism over the past decade, integrative studies are also emerging.
Man, Kallies, and Vasanthakumar review how immune cells regulate adipose tissue homeostasis to control organismal metabolism and thermogenesis [ 22 ]. The regulation of systemic metabolism, including organismal glucose homeostasis, insulin sensitivity, and thermogenesis, is dependent upon proper functioning and intricate cell-cell interactions of the adipose tissue, which includes adipocytes, diverse immune cells, and stromal cells.
The authors discuss how tissue-resident immune cells preserve insulin sensitivity, how immune cell infiltration into adipose tissue drives insulin resistance, and the adipose tissue niches that mediate immune-stromal cell crosstalk.
The authors also discuss the immune and inflammatory basis of obesity and regulation of thermogenesis, and how restoring immune balance in adipose tissue is a promising approach to treat metabolic inflammation and insulin resistance. Diet plays a crucial role in metabolic homeostasis but can also shape immunity and cancer therapy.
Prendeville and Lynch review the roles of lipid metabolism in tumor and immune cells [ 23 ]. The authors first provide an overview of lipid uptake, de novo synthesis, and degradation, and their pro-tumorigenic roles in cancer development and metastasis.
The authors then discuss the impact of lipids at shaping immune cells in the TME, especially recent studies revealing lipid-mediated inhibition of CD8 T cell and NK cell function but their surprising roles in supporting immunosuppression mediated by regulatory T Treg cells, γδ T cells and tumor-associated macrophages.
Given the increased risk of many cancers associated with obesity, understanding the relationship between dietary lipids, tumor cells, and immune cells is important in the context of obesity and cancer therapy. Collectively, these three review articles shed new light on the integration of intracellular network, intercellular interactions, and organismal immunometabolism, and the effects on immunity, metabolism, and cancer.
In conclusion, this series of reviews highlight that the coordination of metabolic programs with nutrient inputs, signal transduction, cell fate, tissue adaptation, and systemic homeostasis is a fundamental event in immunity, physiology, and pathophysiology.
Continuous exploration of immunometabolism, especially by interdisciplinary approaches, promises to open new avenues for therapeutic targeting of metabolic pathways to treat human disease. Chapman NM, Chi H.
Metabolic adaptation of lymphocytes in immunity and disease. Article CAS Google Scholar. Lercher A, Baazim H, Bergthaler A. Systemic immunometabolism: challenges and opportunities.
Chapman NM, Boothby MR, Chi H. Metabolic coordination of T cell quiescence and activation. Nat Rev Immunol. Trim WV, Lynch L. Immune and non-immune functions of adipose tissue leukocytes.
Marchingo JM, Cantrell DA. Protein synthesis, degradation, and energy meta bolism in T cell immunity. Cell Mol Immunol. Heintzman DR, Fisher EL, Rathmell JC. Microenvironmental Inflfluences on T Cell Immunity in Cancer and Inflflammation.
Lee MS, Bensinger SJ. Reprogramming cholesterol metabolism in macrophages and its role in host defense against cholesterol-dependent cytolysins. Chou WC, Rampanelli E, Li X, Ting JP.
Impact of intracellular innate immune receptors on immunometabolism. Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, et al.
The CD28 signaling pathway regulates glucose metabolism. Bian Y, Li W, Kremer DM, Sajjakulnukit P, Li S, Crespo J, et al.
Functionn high-level Avocado Beauty Tips have shown fuunction metabolism of immune cells Metabolism and immune function their effector function to be closely connected. This opinion article will summarize some of Metabolism and immune function groundbreaking studies that established the field of immune metabolism and highlight pioneering metabolic studies that increased our understanding of allergic pathology and introduced potential treatment targets. A timeline of the discussed studies is provided in Figure 1. Figure 1. Timeline of pioneering and breakthrough papers that have helped form the field of immune metabolism.
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