Maliha Tanjum Chowdhury Deneb
Junior
School of Life Sciences
Independent University, Bangladesh
July 30th, 2019
The remarkable ability of immune cells to alter their functions upon activation is a phenomenon that is well known to most biologists. When we think of cellular differentiation or activation, our minds typically drift to the explanation that it is due to changes in gene expression. While it is true that the systematic reprogramming of gene expression is key to transitioning between cellular states, some exciting recent studies times have added another layer of understanding by showing that phenotypic changes in the context of immune cells are also often accompanied by metabolic changes. But before we dive into some of this recent work, some context is necessary.
Innate immune cells constantly patrolling our tissues recognize threats on the basis of special structures that are unique to various classes of pathogens, collectively known as pathogen-associated molecular patterns (PAMPs). For instance, lipopolysaccharide serves as a signature of Gram-negative bacteria. This recognition is mediated by receptors on innate immune cells called pattern recognition receptors (PRRs). In contrast, adaptive immune cells, (B and T cells), upon initial activation, take a few days to learn to recognize antigens - unique signatures associated with specific pathogens - via B cell receptors (antibodies), and T cell receptors (TCRs). These cells retain memory and act rapidly upon reinfection.
It is increasingly evident that specific metabolic pathways are more suited to support different immune states. A well-established example is that of macrophages [1] - innate immune cells which are among the first responders during infection. Macrophages have multiple, mainly two, activated states. An initial activation by pathogens results in M1 or classically activated macrophages, which ramp up inflammation. Inflammation refers to the migration of immune cells to an infected site and the accompanying release of various chemicals to target pathogens. As part of this process, M1 macrophages metabolize the amino acid arginine to produce nitric oxide – a toxic product to kill pathogens – via the enzyme nitric oxide synthase. However, as the infection progresses and the pathogens are cleared, the macrophages switch to M2 or alternatively activated macrophages, which are dedicated to repair collateral damage caused by inflammation, and these cells now metabolize arginine using the enzyme arginase 1 to produce ornithine – an amino acid that is used for tissue re-modelling. Such interplay between immunity and metabolism is now being referred to as immunometabolism. Let us now delve into three recent studies which deal with exciting findings in the field of immunometabolism.
The first of these studies explored changes in metabolic states of immune cells in the context of Mycobacterium tuberculosis infections [2]. Previous research had shown that most immune cell types, upon activation, adopt an alternative metabolic pathway known as aerobic glycolysis to generate energy over the conventional TCA cycle and oxidative phosphorylation. This alternative pathway, which produces lactate even in the presence of oxygen, is much more effective at producing a substantial amount of energy in a short time, even though the amount of energy produced per glucose molecule is less than what is produced via the conventional route. Immune effector cells appear to favor speed over efficiency in order to meet the towering demands of quickly producing signals, mediating downstream activation of other immune cells, and killing pathogens.
The study first established that M. tuberculosis infection induces a shift to the aerobic glycolytic pathway in human peripheral blood mononuclear cells (PBMCs, which include lymphocytes). They then showed that M. tuberculosis infection activates the AKT-mTOR pathway, a cell signaling pathway known to trigger glucose metabolism, among other cellular processes, in response to signals like growth factors and oxidative stress. Chemical inhibition of this pathway resulted in low lactate levels and poor inflammatory cytokine release to fight the infection both in mice and in human PBMCs, thereby establishing a role for the AKT-mTOR pathway in aerobic glycolysis induction as well as immune activation. They also showed that glycolysis induction by M. tuberculosis is dependent on a receptor called TLR2, which recognizes components of the bacterial cell wall. These results indicate that enzymes that are part of this metabolic pathway could perhaps be targeted to bring about a stronger host immune response while fighting tuberculosis, if needed.
A more recent study, published in 2018 [3] explored metabolic rewiring of an adaptive immune cell type called T cells. They were using human cells. T cells have a wide-range of functions, and numerous sub-types which facilitate these functions. Some T cell types contribute to inflammation, and/or killing of infected cells upon detection of pathogens, while others, broadly grouped together as T regulatory (Treg) cells suppress the production of, and activation by inflammatory signals. The Treg cells are important because they prevent the system from going overboard and causing damage to organs and tissues of the body. Differentiation into Treg cells is known to be dependent on a transcription factor called Foxp3, and individuals with defects in Foxp3 are poorly tolerized to a range of self-antigens, giving rise to several types of autoimmune disorders.
Now, a large proportion of Treg cells belong to a larger class of T cells called CD4 positive T cells. CD4 positive T cells exhibit phenotypic plasticity, meaning that they can interchange between different states that are suited to fighting different classes of pathogens, as well as regulatory states. In the 2018 study, the authors reported the transformation of an inflammatory T cell type called T helper type 1 cells to Treg-like cells (dubbed TH1reg cells) by resting the cells in the absence of activation of their T cell receptors before activating the receptors in the presence of TGF-β (a growth factor involved in the normal development of Treg cells from progenitors, and in wound healing). This makes physiological sense, as the progressive clearance of pathogens and their associated antigens after an infection would be expected to result in less frequent T cell receptor stimulation, and TGF-β levels may increase due to tissue damage from inflammation.
The authors went on to find that the treatment elevated Foxp3 expression through a change in metabolic regulation, leading to the Treg-like phenotype. In the absence of receptor activation, there is reduced mTOR signaling in the T cells, and this allows TGF-β-mediated elevation of Foxp3 expression while also making the cells switch from glycolysis to oxidative phosphorylation as the mode of energy generation. While the molecular mechanism connecting the metabolic switch and TGF-β-mediated expression of Foxp3 needs to be further explored, this study again points to the possibility of targeting metabolic or signaling pathways, in this case to curb inflammatory T cells implicated in autoimmune disorders and immunopathologies.
Our third and final recent study [4], published just this year, deals with a very interesting twist on the role of innate immunity in battling cancer. Cancer cells arise from unwanted mutations occuring in normal cells and causing them to divide uncontrollably. Therefore, by default, they express most if not all of the normal cell surface proteins that are known in the body as self-antigens. One such antigen, which acts as a “don’t-eat-me” signal is the CD47 protein. “Don’t-eat-me” implies that these proteins inhibit macrophages from phagocytizing (eating) the individual’s own cells. Recall that macrophages are phagocytic cells that have two distinct phenotypes – either the pro-inflammatory M1, or the anti-inflammatory M2. M1 macrophages have ways of detecting and killing cancer cells despite the “don’t-eat-me” signal. But in the case of many tumors, macrophages surrounding the tumor take on an M2-like phenotype, and produce cell proliferation signals that may assist both tumor progression and immunosuppression.
In this regard, this study shows that stimulation of the PRR, the Toll-like receptor 9 (TLR 9), by CpG oligonucleotide (a DAMP produced due to cell damage and cancerous growth) causes a shift in the central carbon metabolism of mouse macrophages to a state requiring fatty acid oxidation. This allows overriding of the “don’t-eat-me” signal and phagocytosis of the cancer cells expressing CD47. Interestingly, this does not require differentiation into an M1 state. Fatty acid oxidation, and the accompanying rewiring of the TCA cycle to support this oxidative state, somehow facilitate the anti-tumor activity of the macrophages. Therefore, manipulation of the carbon metabolism pathway of the macrophages is highlighted as a possible therapeutic mechanism to fight cancer. However, the problem is that human macrophages lack the TLR 9 receptor, and so the challenge of inducing such changes in mode and implementing them clinically in humans remains and is demanding of further research.
In the papers discussed in this piece, the scientists triggered and recorded metabolic changes in immune cells simply by using the right kinds of receptor stimulation and cytokines, but these findings barely scratch the surface. In the future, it might be possible to manipulate immune phenotypes by directly targeting metabolic pathways through enzymes and enzyme blockers.
References:
[1] K. Ley, “M1 Means Kill; M2 Means Heal,” J. Immunol., vol. 199, no. 7, p. 2191, Oct. 2017.
[2] E. Lachmandas et al., “Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells,” Eur. J. Immunol., vol. 46, no. 11, pp. 2574–2586, Nov. 2016.
[3] M. Kanamori, H. Nakatsukasa, M. Ito, S. Chikuma, and A. Yoshimura, “Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status,” Int. Immunol., vol. 30, no. 8, pp. 357–373, Jul. 2018.
[4] M. Liu, R. S. O’Connor, S. Trefely, K. Graham, N. W. Snyder, and G. L. Beatty, “Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47−mediated ‘don’t-eat-me’ signal,” Nat. Immunol., vol. 20, no. 3, pp. 265–275, Mar. 2019.
Maliha is a weirdo who somehow believes she's from a different planet. But she likes Earth just fine, and is fascinated by the science and beauty of life and has made it her purpose to explore it. Besides this, her most burning desires include becoming a synthetic biologist/ genetic engineer and running away with a heavy metal band.
Junior
School of Life Sciences
Independent University, Bangladesh
July 30th, 2019
The remarkable ability of immune cells to alter their functions upon activation is a phenomenon that is well known to most biologists. When we think of cellular differentiation or activation, our minds typically drift to the explanation that it is due to changes in gene expression. While it is true that the systematic reprogramming of gene expression is key to transitioning between cellular states, some exciting recent studies times have added another layer of understanding by showing that phenotypic changes in the context of immune cells are also often accompanied by metabolic changes. But before we dive into some of this recent work, some context is necessary.
Innate immune cells constantly patrolling our tissues recognize threats on the basis of special structures that are unique to various classes of pathogens, collectively known as pathogen-associated molecular patterns (PAMPs). For instance, lipopolysaccharide serves as a signature of Gram-negative bacteria. This recognition is mediated by receptors on innate immune cells called pattern recognition receptors (PRRs). In contrast, adaptive immune cells, (B and T cells), upon initial activation, take a few days to learn to recognize antigens - unique signatures associated with specific pathogens - via B cell receptors (antibodies), and T cell receptors (TCRs). These cells retain memory and act rapidly upon reinfection.
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| Immune cells chasing down microbes. Ilora Shabnam Kheya |
It is increasingly evident that specific metabolic pathways are more suited to support different immune states. A well-established example is that of macrophages [1] - innate immune cells which are among the first responders during infection. Macrophages have multiple, mainly two, activated states. An initial activation by pathogens results in M1 or classically activated macrophages, which ramp up inflammation. Inflammation refers to the migration of immune cells to an infected site and the accompanying release of various chemicals to target pathogens. As part of this process, M1 macrophages metabolize the amino acid arginine to produce nitric oxide – a toxic product to kill pathogens – via the enzyme nitric oxide synthase. However, as the infection progresses and the pathogens are cleared, the macrophages switch to M2 or alternatively activated macrophages, which are dedicated to repair collateral damage caused by inflammation, and these cells now metabolize arginine using the enzyme arginase 1 to produce ornithine – an amino acid that is used for tissue re-modelling. Such interplay between immunity and metabolism is now being referred to as immunometabolism. Let us now delve into three recent studies which deal with exciting findings in the field of immunometabolism.
The first of these studies explored changes in metabolic states of immune cells in the context of Mycobacterium tuberculosis infections [2]. Previous research had shown that most immune cell types, upon activation, adopt an alternative metabolic pathway known as aerobic glycolysis to generate energy over the conventional TCA cycle and oxidative phosphorylation. This alternative pathway, which produces lactate even in the presence of oxygen, is much more effective at producing a substantial amount of energy in a short time, even though the amount of energy produced per glucose molecule is less than what is produced via the conventional route. Immune effector cells appear to favor speed over efficiency in order to meet the towering demands of quickly producing signals, mediating downstream activation of other immune cells, and killing pathogens.
The study first established that M. tuberculosis infection induces a shift to the aerobic glycolytic pathway in human peripheral blood mononuclear cells (PBMCs, which include lymphocytes). They then showed that M. tuberculosis infection activates the AKT-mTOR pathway, a cell signaling pathway known to trigger glucose metabolism, among other cellular processes, in response to signals like growth factors and oxidative stress. Chemical inhibition of this pathway resulted in low lactate levels and poor inflammatory cytokine release to fight the infection both in mice and in human PBMCs, thereby establishing a role for the AKT-mTOR pathway in aerobic glycolysis induction as well as immune activation. They also showed that glycolysis induction by M. tuberculosis is dependent on a receptor called TLR2, which recognizes components of the bacterial cell wall. These results indicate that enzymes that are part of this metabolic pathway could perhaps be targeted to bring about a stronger host immune response while fighting tuberculosis, if needed.
A more recent study, published in 2018 [3] explored metabolic rewiring of an adaptive immune cell type called T cells. They were using human cells. T cells have a wide-range of functions, and numerous sub-types which facilitate these functions. Some T cell types contribute to inflammation, and/or killing of infected cells upon detection of pathogens, while others, broadly grouped together as T regulatory (Treg) cells suppress the production of, and activation by inflammatory signals. The Treg cells are important because they prevent the system from going overboard and causing damage to organs and tissues of the body. Differentiation into Treg cells is known to be dependent on a transcription factor called Foxp3, and individuals with defects in Foxp3 are poorly tolerized to a range of self-antigens, giving rise to several types of autoimmune disorders.
Now, a large proportion of Treg cells belong to a larger class of T cells called CD4 positive T cells. CD4 positive T cells exhibit phenotypic plasticity, meaning that they can interchange between different states that are suited to fighting different classes of pathogens, as well as regulatory states. In the 2018 study, the authors reported the transformation of an inflammatory T cell type called T helper type 1 cells to Treg-like cells (dubbed TH1reg cells) by resting the cells in the absence of activation of their T cell receptors before activating the receptors in the presence of TGF-β (a growth factor involved in the normal development of Treg cells from progenitors, and in wound healing). This makes physiological sense, as the progressive clearance of pathogens and their associated antigens after an infection would be expected to result in less frequent T cell receptor stimulation, and TGF-β levels may increase due to tissue damage from inflammation.
The authors went on to find that the treatment elevated Foxp3 expression through a change in metabolic regulation, leading to the Treg-like phenotype. In the absence of receptor activation, there is reduced mTOR signaling in the T cells, and this allows TGF-β-mediated elevation of Foxp3 expression while also making the cells switch from glycolysis to oxidative phosphorylation as the mode of energy generation. While the molecular mechanism connecting the metabolic switch and TGF-β-mediated expression of Foxp3 needs to be further explored, this study again points to the possibility of targeting metabolic or signaling pathways, in this case to curb inflammatory T cells implicated in autoimmune disorders and immunopathologies.
Our third and final recent study [4], published just this year, deals with a very interesting twist on the role of innate immunity in battling cancer. Cancer cells arise from unwanted mutations occuring in normal cells and causing them to divide uncontrollably. Therefore, by default, they express most if not all of the normal cell surface proteins that are known in the body as self-antigens. One such antigen, which acts as a “don’t-eat-me” signal is the CD47 protein. “Don’t-eat-me” implies that these proteins inhibit macrophages from phagocytizing (eating) the individual’s own cells. Recall that macrophages are phagocytic cells that have two distinct phenotypes – either the pro-inflammatory M1, or the anti-inflammatory M2. M1 macrophages have ways of detecting and killing cancer cells despite the “don’t-eat-me” signal. But in the case of many tumors, macrophages surrounding the tumor take on an M2-like phenotype, and produce cell proliferation signals that may assist both tumor progression and immunosuppression.
In this regard, this study shows that stimulation of the PRR, the Toll-like receptor 9 (TLR 9), by CpG oligonucleotide (a DAMP produced due to cell damage and cancerous growth) causes a shift in the central carbon metabolism of mouse macrophages to a state requiring fatty acid oxidation. This allows overriding of the “don’t-eat-me” signal and phagocytosis of the cancer cells expressing CD47. Interestingly, this does not require differentiation into an M1 state. Fatty acid oxidation, and the accompanying rewiring of the TCA cycle to support this oxidative state, somehow facilitate the anti-tumor activity of the macrophages. Therefore, manipulation of the carbon metabolism pathway of the macrophages is highlighted as a possible therapeutic mechanism to fight cancer. However, the problem is that human macrophages lack the TLR 9 receptor, and so the challenge of inducing such changes in mode and implementing them clinically in humans remains and is demanding of further research.
In the papers discussed in this piece, the scientists triggered and recorded metabolic changes in immune cells simply by using the right kinds of receptor stimulation and cytokines, but these findings barely scratch the surface. In the future, it might be possible to manipulate immune phenotypes by directly targeting metabolic pathways through enzymes and enzyme blockers.
References:
[1] K. Ley, “M1 Means Kill; M2 Means Heal,” J. Immunol., vol. 199, no. 7, p. 2191, Oct. 2017.
[2] E. Lachmandas et al., “Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells,” Eur. J. Immunol., vol. 46, no. 11, pp. 2574–2586, Nov. 2016.
[3] M. Kanamori, H. Nakatsukasa, M. Ito, S. Chikuma, and A. Yoshimura, “Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status,” Int. Immunol., vol. 30, no. 8, pp. 357–373, Jul. 2018.
[4] M. Liu, R. S. O’Connor, S. Trefely, K. Graham, N. W. Snyder, and G. L. Beatty, “Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47−mediated ‘don’t-eat-me’ signal,” Nat. Immunol., vol. 20, no. 3, pp. 265–275, Mar. 2019.
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