Immunometabolism

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Immunometabolism is a branch of biology that studies the interplay between metabolism and immunology in all organisms. In particular, immunometabolism is the study of the molecular and biochemical underpinninngs for i) the metabolic regulation of immune function, and ii) the regulation of metabolism by molecules and cells of the immune system. [1] Further categorization includes i) systemic immunometabolism and ii) cellular immunometabolism. [2] Immunometabolism includes metabolic inflammation:a chronic, systemic, low grade inflammation, orchestrated by metabolic deregulation caused by obesity or aging.

Contents

Immunometabolism first appears in academic literature in 2011, where it is defined as "an emerging field of investigation at the interface between the historically distinct disciplines of immunology and metabolism." [3] A later article defines immunometabolism as describing "the changes that occur in intracellular metabolic pathways in immune cells during activation". [4] Broadly, immunometabolic research records the physiological functioning of the immune system in the context of different metabolic conditions in health and disease. These studies can cover molecular and cellular aspects of immune system function in vitro , in situ , and in vivo, under different metabolic conditions. For example, highly proliferative cells such as cancer cells and activating T cells undergo metabolic reprogramming, increasing glucose uptake to shift towards aerobic glycolysis during normoxia. While aerobic glycolysis is an inefficient pathway for ATP production in quiescent cells, this so-called “Warburg effect” supports the bioenergetic and biosynthetic needs of rapidly proliferating cells. [5]

Signalling and metabolic network

There are many indispensable signalling molecules connected to metabolic processes, which play an important role in both the immune system homeostasis and in the immune response. From these the most significant are mammalian target of rapamycin (mTOR ), liver kinase B1 (LBK1), 5' AMP-activated protein kinase (AMPK), phosphoinositide 3 kinase (PI3K) and protein kinase B (akt). All of the aforementioned molecules together control the most important metabolic pathways in cells like glycolysis, krebs cycle or oxidative phosphorylation. To fully understand how all of these molecules and pathways affect the immune cells, it is first needed to examine the delicate interplay of these molecules. [6] [4]

mTOR

mTOR is a serine/threonine protein kinase, which is found in 2 complexes in cells: mTOR complex 1 and 2 ( mTORC1 and mTORC2 ). mTORC1 is activated through the T cell receptor (TCR) and the costimulatory molecule cluster of differentiation 28 (CD28) engagement. However, it can also be activated by growth factors like IL-7 or IL-2 and by metabolites like glucose or amino acids (leucin, arginine or glutamine). [7] [6] In contrast, there are more gaps as to how mTORC2 pathway functions, but its activation is also achieved through growth factors as exemplified by IL-2. [6]

When activated mTORC1 negatively regulates autophagy (through inhibiting the ULK complex) and shifts the cell towards aerobic glycolysis, glutaminolysis (through activation of c-Myc) and promotes lipid synthesis and mitochondrial remodelling. [7] [6] mTORC2 enhances glycolysis as well, but in contrast to mTORC1, it activates akt, which in turn promotes glucose transporter 1 (GLUT1) membrane deposition. It also further promotes, through other kinases, cell proliferation and survival. [6]

PI3K-akt

PI3K mediates the phosphorylation of phosphatidylinositol-(4,5)-bisphosphate (PIP2) into phosphatidylinositol-(3,4,5)-trisphosphate (PIP3). PIP3 then serves as a scaffold for other proteins, which contain a pleckstrin homology (PH) domain. It can be activated, just like mTOR, through TCR, CD28 and, unlike mTOR, through another costimulatory molecule: Inducible T-cell COStimulator (ICOS). [6]

The present of PIP3 on a membrane recruits many proteins including phosphoinositide-dependent protein kinase 1 (PDK1), which after its phosphorylation together with mTORC2 activates akt, a serine/threonine kinase. As a result akt promotes GLUT1 membrane deposition and akt also inhibits transcription factor forkhead box O (FoxO), whose inactivation acts in synergy with the mTORC2 above mentioned changes. [6] [8]

LBK1-AMPK

Both LBK1 and AMPK are serine/threonine kinases acting predominantly opposingly to the aforementioned molecules. From the two, LBK1's activation is less understood, as it is mainly dependants on cellular localization and on many posttranslational modifications. For instance the above-mentioned akt can stimulate LBK1 inhibition through promoting nuclear retention. When activated, LBK1 can activate, apart from other targets, AMPK, whose activation leads to mTORC1 destabilization. [6] Furthermore, it activates ULK complex, phosphorylates p53 and acetyl-CoA carboxylase (ACC), which promotes autophagy, cell cycle arrest and fatty acids oxidation respectively. Since AMPK can also be activated through adenosine monophosphate (AMP) or by glucose insufficiency, it acts as a sensor of starvation and therefore activates many already mentioned catabolic processes, which is in direct contrast with mTOR, which activates myriad of anabolic processes. [6] [7] [9]

Immune cells

Generally speaking, cells, whose primary objective is their long-term survival or control of inflammation, in terms of energy tend to rely on Krebs cycle and lipid oxidation which are both coupled with functional oxidative phosphorylation. Among these cells we can include naive T cells, memory T cells, regulatory T cells (Tregs), unstimulated innate immune cells like macrophages and M2 macrophages. On the contrary, cells whose main function is proliferation, synthesis of different molecules or propagation of inflammation often prefer glycolysis as a source of energy and metabolites. Therefore, into these cells belong for instance effector T cells and M1 macrophages. [4] [8] [10]

T cells

Naive T cells have to be kept in a permanent state of quiescence, until they encounter their cognate antigen. The quiescence state is sustained by tonic TCR signalling and by IL-7. Tonic TCR signalling is necessary to keep the FoxO transcription factor active, which in turn allows for IL-7R transcription. This enables the T cell to survive and proliferate at a low rate. However, during this tonic TCR signalling proteins, that control metabolism, have to be strictly regulated, because their activation could lead to spontaneous exit of quiescence and differentiation into various T cells subset, as exemplified by the uncontrolled activation of PI3K which causes the development of Th1 or Th2. [11]

Both of the aforementioned signals should lead to the mTOR and akt activation, but in quiescence T cells there are tuberous sclerosis complex (TSC) and phosphatase and tensin homolog (PTEN) acting against their activations. Therefore, a naive T cell dependent predominantly on oxidative phosphorylation and has much lower glucose uptake and ATP production than their activated counterparts (effector T cells). [11] [7] [6]

Quiescence exit begins when a T cell encounters its cognate antigen usually during an infection. The TCR signal together with the costimulation signal lead to downregulation of PTEN and TSC. [11] This causes the phosphorylation cascades of mTOR and akt and many more kinases to be fully activated. These cascades activities result in glucose and glutamine uptake coupled with higher glycolysis and glutaminolysis, which not only supports rapid cell growth, but also further promotes mTOR activation. Furthermore, mTOR stimulates lipid synthesis and mitochondria remodelling, exemplified by increased expression of sterol regulatory element-binding protein (SREBP) and mitochondria undergoing fission, which causes them to function predominantly as biosynthetic hubs, rather than energy production hubs. After their activation and the metabolic reprogramming, T cells compete with one another and consequently, it is very likely that during its effector phase T cells reach a point, where they suffer from lack of nutrients. In such cases AMPK is activated to balance the mTOR signalling and to prevent apoptosis. [11] [6] [4]

The described scheme of quiescence exit holds true for inflammatory T cells subsets like Th1, Th2, Th17 and cytotoxic T cells. However, mTOR activity can be detrimental when we focus on Tregs. This is shown by the fact that in Tregs high activation of mTORC1 coupled with a higher level of glycolysis leads to the failure of Treg lineage commitment. Therefore, in contrast to inflammatory cell subsets, Tregs rely on oxidative phosphorylation fuelled by lipid oxidation. [11] [4] Although, it is important to note that complete suppression of glycolysis leads to enolase (a glycolytic enzyme) binding to a splice variant of Foxp3, which effectively compromises peripheral Tregs abilities to act as immunosuppressive cells. [7] [4]

After the infection is cleared most of the activated T cells succumb to apoptosis. However, few of them survive and develop into the memory T cell subsets. For this development the engagement of costimulatory molecules, like CD28, appears to be crucial, as the co-stimulation manifests in mitochondrial morphology, thus allowing for higher oxidative phosphorylation but also retaining the potential to quickly revert to glycolysis. [12] [13] Moreover, T cell activation causes an overall increase in acetyl-CoA, which is a substrate for the histone acetylation. As a results, many genes are acetylated and therefore accessible to transcription even after the differentiation into memory subsets, hence allowing memory T cells to rapidly re-express some effector related genes. [12] The aforementioned changes allow T cells to become memory cells, but what exactly drives the memory cell differentiation is still under debate, even though IL-15 seems to be necessary for the T cell memory induction. Recently, asymmetric division of mTORC1, during the first divisions after TCR activation, has been shown to drive the memory cell differentiation in those cells which receive lower amount of mTORC1. [12] [13]

Macrophages

Immunometabolism of macrophages is mostly studied in the two opposing populations of macrophages: M1 and M2. M1 macrophages are a pro-inflammatory population induced by LPS or IFNγ. This activation leads, as in the case of T cells, to increase in glycose uptake and glycolysis. What is strikingly different is the Krebs cycle, as in the case of M1 macrophages the cycle is broken at two places. The first break is the conversion of iso-citrate to α-ketoglutarate owing to the downregulation of isocitrate dehydrogenase. Accumulated citrate is subsequently used for lipid and itaconate synthesis, which are both indispensable for M1 macrophages function. The second break at the succinate to fumarate transition occurs probably due to the itaconate production and causes a build up of succinate. This triggers ROS production, which stabilizes HIF-1α. This transcription factor further promotes glycolysis and it is essential for activation of inflammatory macrophages. [10] [4]

M2 macrophages are anti-inflammatory cells which need for their induction IL-4. M2 macrophages metabolism is markedly distinct from M1 macrophages due to their unbroken Krebs cycle, which after their activation is fuelled by upragulated glycolysis, glutaminolysis and fatty acid oxidation. [10] [4] How the fully operational Krebs cycle exactly translates to M2 macrophages functions is still poorly understood, but the upregulated pathways allow for production of intermediates (mainly acetyl-CoA and S-adenosyl methionine), which are needed for histone modifications of genes targeted by IL-4 signalling. [10]

Drug discovery

Immunometabolism is an area of growing drug discovery research investment [14] [15] in numerous areas of medicine, such as for example, in lessening the impact of age-related metabolic dysfunction and obesity on incidence of type 2 diabetes/ cardiovascular disease, cancer, [3] [16] [17] as well as infectious diseases. [18] In recent years, evidence suggests that immunometabolism is implicated in autoimmune disorders. [19] [20] The metabolic alterations on immune system regulation have provided unique insights into disease pathogenesis and development, as well as potential therapeutic targets. [21] [22] [23]

Immunometabolism - from inflammation to sepsis

Sepsis-Related Immunometabolic Paralysis

Sepsis pathophysiology now includes immunometabolic paralysis, a condition marked by severe abnormalities in cellular energy metabolism. This phenomenon affects both the acute and late stages of the disease, playing a critical role in the immune response during sepsis. [24]

Summary

A potentially fatal illness known as sepsis is brought on by the body's overreaction to an infection. Although there is a strong inflammatory response during the early phase of sepsis, [24] [25] immunometabolic paralysis may appear later on and is linked to a bad prognosis for the patient. Shih Chin Cheng and colleagues have conducted recent research that explores the complex interplay between cellular metabolism and the immune response in sepsis. [24]

Important Results

• 1. Transition from Oxidative Phosphorylation to Aerobic Glycolysis: The Warburg effect, which occurs during the acute stage of sepsis, is characterized by a change from oxidative phosphorylation to aerobic glycolysis. [24] [26] One of the key mechanisms in the first activation of the host defense against infections is this metabolic change. [24]

• 2. Impaired Energy Metabolism in Leukocytes: It was shown that patients experiencing acute sepsis exhibited extensive impairments in cellular energy metabolism, which impacted leukocyte glycolysis and oxidative metabolism. [24] [27] The ailment known as immunometabolic paralysis is associated with a compromised capacity to react to secondary stimulus. [28] [24]

• 3. IFN-γ's Function in Restoring Glycolysis: Interferon-gamma, or IFN-γ, is being explored as a possible treatment option IFN-γ therapy partially restored glycolysis [24] , [29] in tolerant monocytes, as demonstrated by in vitro tests, demonstrating its ability to mitigate the metabolic abnormalities linked to immunotolerance. [24]

Therapeutic Implications

The work emphasizes how cellular metabolism in sepsis might be targeted therapeutically. Although few medicines possessing metabolic-regulatory properties have been investigated, the study emphasizes how important it is to comprehend and treat immunometabolic paralysis in order to improve outcomes for individuals suffering from sepsis. [24]

Conclusion

To sum up, the research conducted by Cheng and colleagues provides significant understanding of the intricate relationship between immune response and cellular metabolism in sepsis. A crucial role for immunometabolic paralysis—a condition marked by impaired energy metabolism—in the development and cure of sepsis is revealed. It appears that more investigation and testing of therapeutic approaches aimed at cellular metabolism will help to improve the management of sepsis. [24]


Related Research Articles

<span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

<span class="mw-page-title-main">Kinase</span> Enzyme catalyzing transfer of phosphate groups onto specific substrates

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. This transesterification produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

<span class="mw-page-title-main">AMP-activated protein kinase</span> Class of enzymes

5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 in yeast, and SnRK1 in plants. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic β-cells.

G<sub>0</sub> phase Quiescent stage of the cell cycle in which the cell does not divide

The G0 phase describes a cellular state outside of the replicative cell cycle. Classically, cells were thought to enter G0 primarily due to environmental factors, like nutrient deprivation, that limited the resources necessary for proliferation. Thus it was thought of as a resting phase. G0 is now known to take different forms and occur for multiple reasons. For example, most adult neuronal cells, among the most metabolically active cells in the body, are fully differentiated and reside in a terminal G0 phase. Neurons reside in this state, not because of stochastic or limited nutrient supply, but as a part of their developmental program.

In oncology, the Warburg effect is the observation that most cancer cells release energy predominantly not through the 'usual' citric acid cycle and oxidative phosphorylation in the mitochondria as observed in normal cells, but through a less efficient process of 'aerobic glycolysis' consisting of a high level of glucose uptake and glycolysis followed by lactic acid fermentation taking place in the cytosol, not the mitochondria, even in the presence of abundant oxygen. This observation was first published by Otto Heinrich Warburg, who was awarded the 1931 Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme". The precise mechanism and therapeutic implications of the Warburg effect, however, remain unclear.

<span class="mw-page-title-main">Protein kinase B</span> Set of three serine/threonine-specific protein kinases

Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.

mTOR Mammalian protein found in humans

The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.

<span class="mw-page-title-main">Glyceraldehyde 3-phosphate dehydrogenase</span> Enzyme of the glycolysis metabolic pathway

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<span class="mw-page-title-main">Tumor metabolome</span>

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Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of IL-2 in T cells but has since been found to play an important role in regulating many more body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders.

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<span class="mw-page-title-main">RPTOR</span> Protein-coding gene in humans

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<span class="mw-page-title-main">PKM2</span> Protein-coding gene in the species Homo sapiens

Pyruvate kinase isozymes M1/M2 (PKM1/M2), also known as pyruvate kinase muscle isozyme (PKM), pyruvate kinase type K, cytosolic thyroid hormone-binding protein (CTHBP), thyroid hormone-binding protein 1 (THBP1), or opa-interacting protein 3 (OIP3), is an enzyme that in humans is encoded by the PKM2 gene.

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mTORC1 Protein complex

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mTOR Complex 2 (mTORC2) is an acutely rapamycin-insensitive protein complex formed by serine/threonine kinase mTOR that regulates cell proliferation and survival, cell migration and cytoskeletal remodeling. The complex itself is rather large, consisting of seven protein subunits. The catalytic mTOR subunit, DEP domain containing mTOR-interacting protein (DEPTOR), mammalian lethal with sec-13 protein 8, and TTI1/TEL2 complex are shared by both mTORC2 and mTORC1. Rapamycin-insensitive companion of mTOR (RICTOR), mammalian stress-activated protein kinase interacting protein 1 (mSIN1), and protein observed with rictor 1 and 2 (Protor1/2) can only be found in mTORC2. Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.

<span class="mw-page-title-main">Michael N. Hall</span> American-Swiss molecular biologist

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Hematopoietic stem cells (HSCs) have high regenerative potentials and are capable of differentiating into all blood and immune system cells. Despite this impressive potential, HSCs have limited potential to produce more multipotent stem cells. This limited self-renewal potential is protected through maintenance of a quiescent state in HSCs. Stem cells maintained in this quiescent state are known as long term HSCs (LT-HSCs). During quiescence, HSCs maintain a low level of metabolic activity and do not divide. LT-HSCs can be signaled to proliferate, producing either myeloid or lymphoid progenitors. Production of these progenitors does not come without a cost: When grown under laboratory conditions that induce proliferation, HSCs lose their ability to divide and produce new progenitors. Therefore, understanding the pathways that maintain proliferative or quiescent states in HSCs could reveal novel pathways to improve existing therapeutics involving HSCs.

References

  1. ↑ Hotamisligil GS (September 2017). "Foundations of Immunometabolism and Implications for Metabolic Health and Disease". Immunity. 47 (3): 406–420. doi:10.1016/j.immuni.2017.08.009. PMC   5627521 . PMID   28930657.
  2. ↑ Lercher A, Baazim H, Bergthaler A (September 2020). "Systemic Immunometabolism: Challenges and Opportunities". Immunity. 53 (3): 496–509. doi:10.1016/j.immuni.2020.08.012. PMC   7491485 . PMID   32937151.
  3. 1 2 Mathis D, Shoelson SE (February 2011). "Immunometabolism: an emerging frontier". Nature Reviews. Immunology. 11 (2): 81–83. doi:10.1038/nri2922. PMC   4784680 . PMID   21469396.
  4. 1 2 3 4 5 6 7 8 O'Neill LA, Kishton RJ, Rathmell J (September 2016). "A guide to immunometabolism for immunologists". Nature Reviews. Immunology. 16 (9): 553–565. doi:10.1038/nri.2016.70. PMC   5001910 . PMID   27396447.
  5. ↑ Andrejeva G, Rathmell JC (July 2017). "Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors". Cell Metabolism. 26 (1): 49–70. doi: 10.1016/j.cmet.2017.06.004 . PMC   5555084 . PMID   28683294.
  6. 1 2 3 4 5 6 7 8 9 10 11 Saravia J, Raynor JL, Chapman NM, Lim SA, Chi H (April 2020). "Signaling networks in immunometabolism". Cell Research. 30 (4): 328–342. doi:10.1038/s41422-020-0301-1. PMC   7118125 . PMID   32203134.
  7. 1 2 3 4 5 Kumar V (August 2018). "T cells and their immunometabolism: A novel way to understanding sepsis immunopathogenesis and future therapeutics". European Journal of Cell Biology. 97 (6): 379–392. doi:10.1016/j.ejcb.2018.05.001. PMID   29773345. S2CID   21731313.
  8. 1 2 Jellusova J (May 2020). "The role of metabolic checkpoint regulators in B cell survival and transformation". Immunological Reviews. 295 (1): 39–53. doi: 10.1111/imr.12855 . PMID   32185805. S2CID   212751998.
  9. ↑ Makowski L, Chaib M, Rathmell JC (May 2020). "Immunometabolism: From basic mechanisms to translation". Immunological Reviews. 295 (1): 5–14. doi:10.1111/imr.12858. PMC   8056251 . PMID   32320073.
  10. 1 2 3 4 van Teijlingen Bakker N, Pearce EJ (May 2020). "Cell-intrinsic metabolic regulation of mononuclear phagocyte activation: Findings from the tip of the iceberg". Immunological Reviews. 295 (1): 54–67. doi: 10.1111/imr.12848 . PMC   10911050 . PMID   32242952. S2CID   214767212.
  11. 1 2 3 4 5 Chapman NM, Boothby MR, Chi H (January 2020). "Metabolic coordination of T cell quiescence and activation". Nature Reviews. Immunology. 20 (1): 55–70. doi:10.1038/s41577-019-0203-y. PMID   31406325. S2CID   199542651.
  12. 1 2 3 Corrado M, Pearce EL (January 2022). "Targeting memory T cell metabolism to improve immunity". The Journal of Clinical Investigation. 132 (1). doi:10.1172/JCI148546. ISSN   0021-9738. PMC   8718135 . PMID   34981777.
  13. 1 2 Salmond RJ (2018). "mTOR Regulation of Glycolytic Metabolism in T Cells". Frontiers in Cell and Developmental Biology. 6: 122. doi: 10.3389/fcell.2018.00122 . ISSN   2296-634X. PMC   6167959 . PMID   30320109.
  14. ↑ "Roche to spend around $800 million on immunometabolism collaboration". www.thepharmaletter.com. Retrieved 2020-03-03.
  15. ↑ Taylor C. "Biopharma start-up co-founded by TCD professor raises $30m". The Irish Times. Retrieved 2020-03-03.
  16. ↑ Rena G, Lang CC (January 2018). "Repurposing Metformin for Cardiovascular Disease". Circulation. 137 (5): 422–424. doi: 10.1161/CIRCULATIONAHA.117.031735 . PMID   29378754.
  17. ↑ Goodbody W (2018-03-28). "Discovery over treatment of inflammation in cells". RTÉ.
  18. ↑ Rosenberg G, Yehezkel D, Hoffman D, Mattioli CC, Fremder M, Ben-Arosh H, et al. (January 2021). "Host succinate is an activation signal for Salmonella virulence during intracellular infection". Science. 371 (6527): 400–405. Bibcode:2021Sci...371..400R. doi:10.1126/science.aba8026. PMID   33479153. S2CID   231666432.
  19. ↑ Freitag J, Berod L, Kamradt T, Sparwasser T (November 2016). "Immunometabolism and autoimmunity". Immunology and Cell Biology. 94 (10): 925–934. doi: 10.1038/icb.2016.77 . PMID   27562063. S2CID   3168902.
  20. ↑ Perl A (December 2017). "Review: Metabolic Control of Immune System Activation in Rheumatic Diseases". Arthritis & Rheumatology. 69 (12): 2259–2270. doi:10.1002/art.40223. PMC   5711528 . PMID   28841779.
  21. ↑ Rhoads JP, Major AS, Rathmell JC (May 2017). "Fine tuning of immunometabolism for the treatment of rheumatic diseases". Nature Reviews. Rheumatology. 13 (5): 313–320. doi:10.1038/nrrheum.2017.54. PMC   5502208 . PMID   28381829.
  22. ↑ Stathopoulou C, Nikoleri D, Bertsias G (June 2019). "Immunometabolism: an overview and therapeutic prospects in autoimmune diseases". Immunotherapy. 11 (9): 813–829. doi:10.2217/imt-2019-0002. PMID   31120393. S2CID   162182686.
  23. ↑ Puniya BL, Amin R, Lichter B, Moore R, Ciurej A, Bennett SJ, Shah AR, Barberis M, Helikar T (January 2021). "Integrative computational approach identifies drug targets in CD4+ T-cell-mediated immune disorders". npj Systems Biology and Applications. 7 (4): 4. doi:10.1038/s41540-020-00165-3. PMC   7822845 . PMID   33483502.
  24. 1 2 3 4 5 6 7 8 9 10 11 Cheng, S. C., Scicluna, B. P., Arts, R. J., Gresnigt, M. S., Lachmandas, E., Giamarellos-Bourboulis, E. J., Kox, M., Manjeri, G. R., Wagenaars, J. A., Cremer, O. L., Leentjens, J., van der Meer, A. J., van de Veerdonk, F. L., Bonten, M. J., Schultz, M. J., Willems, P. H., Pickkers, P., Joosten, L. A., van der Poll, T., & Netea, M. G. (2016). Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nature immunology, 17(4), 406–413. https://doi.org/10.1038/ni.3398
  25. ↑ Xiao, H., Siddiqui, J., & Remick, D. G. (2006). Mechanisms of mortality in early and late sepsis. Infection and immunity, 74(9), 5227–5235. https://doi.org/10.1128/IAI.01220-05
  26. ↑ Bar-Or, D., Carrick, M., Tanner, A., 2nd, Lieser, M. J., Rael, L. T., & Brody, E. (2018). Overcoming the Warburg Effect: Is it the key to survival in sepsis?. Journal of critical care, 43, 197–201. https://doi.org/10.1016/j.jcrc.2017.09.012
  27. ↑ Dreschers, S., Ohl, K., Lehrke, M. et al. Impaired cellular energy metabolism in cord blood macrophages contributes to abortive response toward inflammatory threats. Nat Commun 10, 1685 (2019). https://doi.org/10.1038/s41467-019-09359-8
  28. ↑ Wiersinga, W. J., & van der Poll, T. (2022). Immunopathophysiology of human sepsis. EBioMedicine, 86, 104363. https://doi.org/10.1016/j.ebiom.2022.104363
  29. ↑ Stienstra, R., Netea-Maier, R. T., Riksen, N. P., Joosten, L. A. B., & Netea, M. G. (2017). Specific and Complex Reprogramming of Cellular Metabolism in Myeloid Cells during Innate Immune Responses. Cell metabolism, 26(1), 142–156. https://doi.org/10.1016/j.cmet.2017.06.001
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