Interplay Between Metabolic Sensors and Immune Cell Signaling
The immune system, like all other systems, responds to perturbations of the baseline, homeostatic functioning of immune cells. These perturbations come in the form of infection, tumors, autoantigens, and can occur after mismatched transplantation. During response, immune cells alter their metabolic activities. However, the subsets of the same cell type differ to distinctively associate specific immune function to a particular metabolic profile. The response is mounted as a joint function of metabolic receptor and immune receptor signaling that target various metabolic pathways: glycolysis the pentose phosphate pathway; oxidative phosphorylation; beta-oxidation of fatty acids and transamination. The products from these cycles are integrated in the tricarboxylic acid cycle. However, many more pathways lead to many secondary metabolites that are not directly related to energy derivation or maintaining structure of the cells. These secondary metabolites can again work in an autocrine manner to re-tune the immune cells to optimize their restorative effector functions.
KeywordsLeishmania Macrophage metabolism Immunometabolomic Neutrophil metabolism Lymphocyte metabolism Metabolic regulation of immune response
The work has been recommended by Infect-ERA (Project INLEISH) and was funded by the Department of Biotechnology, New Delhi, Government of India. The grant number is BT/IN/Infect-ERA/33/BS/2016-17.
T cells anergy is a tolerance mechanism by which lymphocytes become intrinsically refractory to antigenic sensitization, but do not undergo apoptosis readily. Instead, they exhibit loss in functionality and a state of hyporesponsiveness in their effector functions. Anergy affects both CD4+ and CD8+ lymphocytes, and two major mechanisms underlying this obscure phenomenon are documented: (1) Clonal anergy, which is predominantly characterized as growth arrest. This type of anergy arises from incomplete T cell activation and is observed in T cells which have undergone prior activation. Mechanistically, blockade in the Ras/MAPK pathway might be responsible for such observed numbness, and, evidently, it has been suggested that IL-2 or anti-OX40 signaling could reverse such a phenotype. (2) Adaptive tolerance, which represents a more generalized inhibition of proliferation and effector functions. This type of anergy is initiated in naïve T cell in vivo by an inadequate environmental stimulus of deficit costimulatory signals provided by CD28 or dominant inhibitory signals from coinhibitory molecules such as PD-1 and PD-L1 or even both. It has been shown that blockade of the interaction between PD-1 and its ligands PD-L1 and PD-L2 prevents anergy induction in iNKT cells. Adaptive tolerance can be induced in the thymus as well as in peripheral lymphoid organs. When persistent antigen is encountered, T cells block receptor tyrosine kinase activity, which ablates calcium mobilization, and also another independent mechanism involving the IL-2 signaling cascade.
In the metazoan body, the immune system carries out specialized functions that coordinate several responses when encounters with a foreign microorganism/their derivatives take place. A myriad of such responses includes the induction of an inflammatory environment and coordinated execution of genes responsible for the activation and mobilization of cells of the immune system. Such highly tailored responses to external stimulus are mediated by, neutrophils, dendritic cells, macrophages, T cells, and B cells, along with other immune cells. These immune cells experiences dramatic shifts in their metabolic profiles upon activation, making them adequate to combat the infection directly (by synthesizing antimicrobial peptides, nitric oxide, and ROS) and indirectly (pleiotropic factors such as chemokines and cytokines, which attract and activate cells of the adaptive immune system), and, thus, making them first responders to any exogenous pathogenic stimulus.
The cellular economy is monetized by adenosine triphosphate (ATP). ATP is generated in a cell by two major pathways, glycolysis and oxidative phosphorylation. Depending upon the requirement of a cell, metabolism can shift towards the anabolic module (the de novo or salvage construction of molecules required for growth and biomass production) or the catabolic module (the breakdown of macromolecules into yet smaller molecules for the production of energy). The glycolytic pathway converts glucose into pyruvate via a series of intermediate metabolites that can enter other pathways (such as the pentose phosphate pathway PPP) and contribute to biosynthesis and cell growth. Glycolysis also leads to the conversion of two molecules of coenzyme NAD+ to NADH, and the overall process can be summarized as:Glucose + 2NAD + + 2ADP + 2P i ➔ Pyruvate + 2NADH + 2ATP + 2H + + 2H 2 O
Histone tails are positively charged, owing to amine groups present on their lysine and arginine AA residues. These positive charges help the histone tails to interact with and bind to the negatively charged phosphate groups on the DNA backbone. HDACs are a class of enzymes that remove acetyl groups (O=C–CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This decreased binding allows chromatin expansion, permitting genetic transcription to take place.
Insulin is secreted by β cells in the pancreas contained within islets clusters. Insulin is synthesized and secreted by these cells. The blood sugar level spikes after meals; in response, this provides a neuroendocrine stimulus to the pancreas (by the hypothalamus) to secrete insulin into the blood. There, insulin helps muscle, fat, and the liver absorb glucose from the bloodstream, lowering blood glucose levels. Insulin stimulates hepatocytes and muscle cells to store excess glucose in a process known as gluconeogenesis. Insulin also provides a positive feedback to hepatocytes to reduce glucose production in order to maintain glucose homeostasis in the body. In case of insulin resistance, muscle, adipose cells, and hepatocytes do not respond optimally to insulin and, thus, fail to absorb glucose from the bloodstream. The reasons for insulin resistance can be numerous, such as high fat intake causes obesity and obesity-induced inflammation, in case of cardiovascular diseases, insufficient physical exercise, excess FA-induced mitochondrial dysfunction, and many other factors, such as lifestyle, etc. As a consequence of this, β cells in the pancreas try to meet the elevated demand for insulin by producing more insulin but, consequentially over time, insulin resistance can lead to type 2 diabetes because, ultimately, β cells fail to supply enough insulin to the body. As a result, blood glucose levels build up, leading to serious metabolic syndromes.
As the concept of metabolic regulation of the immune system gained wider acceptance over years, the importance of bidirectional regulation of the immune system and their effector functions dictated by their metabolic status became clearer. Activated T cells significantly upregulate glucose, amino acid, and iron uptakes, compensating the requirements for active biosynthesis of nascent proteins, DNA, and lipids that are linked to proliferation and growth. To undergo a polarization under signals like cytokines, inflammatory mediators, or direct physical engagement via PAMP-TLR or the MHC–Peptide–TCR complex with pathogenic moieties, it is mandatory for immune cells to rewire their metabolic network. These dramatic metabolic transitions in T cells that are crucial for supporting their activation and function are termed as ‘metabolic reprogramming’. The effects of immune cells include cytokine activation of cells such as adipocytes and hepatocytes, which are the central hub of mediating systemic metabolic changes (for example, in metabolic disorders such as type 2 diabetes and obesity-induced inflammation). In addition, the concept of reciprocal regulation of immune cells by host-commensal microbiota-derived metabolites and nutritive status of the body influencing the immune cells is now very well documented. Such multifaceted chemical interactions between different cells of the body with lymphocytes and macrophages eventually shape the immune responses significantly.
Glycolysis and the TCA cycle help maintain the NAD+–NADH redox balance in a cell and the NADH and FADH2 molecules are used to donate electrons to the electron transport chain on the inner membrane of a mitochondrion for oxidative phosphorylation. For each molecule of FADH2 or NADH oxidized, two or three molecules of ATP, respectively, are generated. Redox reactions in the oxidative phosphorylation sequentially transfer electrons to generate a proton (H+) gradient across the inner membrane of mitochondria, which drives the synthesis of ATP. Although immune cells utilize other metabolic pathways such as the pentose phosphate pathway, glutaminolysis, and fatty acid oxidation, the common molecule integrating these pathways is glucose.
Generates ribose for nucleotide synthesis. During this process, NADH+ is reduced to NADPH, forming the cofactor for ROS generation via the NADPH oxidase (NPhox) system in phagocytic cells.
A primary metabolite is a kind of metabolite that is directly involved in normal growth, development, and reproduction. It usually performs a physiological function in the organism (i.e., an intrinsic function). A primary metabolite is typically present in many organisms or cells. Major examples include amino acids (AA), alcohols, vitamins, polyols, organic acids, and nucleotides. Metabolites from external sources such as products from microbial growth are also primary metabolites.
Acetyl-CoA can also undergo alternate fates, i.e., its conversion to lactate, which is excreted from cells. Acetyl-CoA (2C) enters the TCA cycle to combine with oxaloacetic acid (4C) and yield citrate (6C). Through a sequential set of reactions, citrate is completely oxidized to CO2 and oxaloacetic acid is regenerated. The TCA cycle completes the oxidation of glucose to six molecules of CO2, generating two molecules of GTP (guanosine triphosphate), ten molecules of NADH, and two molecules of reduced FAD (FADH2). The TCA cycle provides intermediates that can be exported to cytosol for fatty acid synthesis. The NADH thus formed as a product in the above step needs to be recycled. In anaerobic organisms or hypoxic mammalian cells, NAD+ is regenerated from NADH by the conversion of pyruvate to lactate. In aerobic organisms, the NADH and pyruvate that are generated by glycolysis are transported to mitochondria. One carbon of each pyruvate molecule is released as carbon dioxide (CO2) and one molecule of NADH is generated; the remaining two carbons are added to a carrier, coenzyme A, to yield acetyl-CoA, which acts as a connecting link between glycolysis and the TCA cycle.
A chemical reaction that transfers an amino group to a ketoacid to form new amino acids. This pathway is responsible for the deamination of most amino acids. During glutaminolysis, α-ketoglutarate is generated from glutamine. Glutamine thus plays dual functions: replenishing the exhausted intermediates of the TCA cycle and complete oxidation to generate ATP. The choice that immune cells make to divert glutaminolysis in either direction depends on the energy requirements during states like infection and homeostasis. The β-oxidation of fatty acids also yields acetyl-CoA, which is burnt through the TCA cycle.
Under oxygen-plentiful conditions, non-proliferative tissues preferentially metabolize glucose to pyruvate via glycolysis, and then completely oxidize most of the pyruvate in the mitochondria to CO2 and generate energy via a process known as oxidative phosphorylation (OxPhos). Because the oxygen is required as the final electron acceptor to completely oxidize glucose, this process is obligatorily aerobic. Thus, when hypoxic conditions are encountered, cells divert the pyruvate generated via glycolysis away from OxPhos by generating lactose. Lactate production allows glycolysis to continue (since NADH cycles back to NAD+), but limits ATP production in comparison to OxPhos. Sir Otto Warburg made a pioneering discovery that cancer cells are inherently skewed towards converting most glucose to lactate in spite of utopic oxygenation. This aerobic glycolysis is also reported to occur in normal proliferative cells besides transformed malignant cells. While this mode of generating energy is far less efficient as compared to OxPhos, it justifies the explanation for faster glucose utilization rates exhibited by cancerous cells. Another plausible explanation for enhanced conversion of glucose to lactate by tumor cells is that HIF-1α is stabilized and accumulates in cytosol upon hypoxic induction. HIF-1α transactivates the glycolytic genes, as well as activating the PDK1 gene, which is responsible for the conversion of pyruvate to acetyl-CoA. Acetyl-CoA enters the TCA cycle, which donates electrons to mitochondrial respiratory chain complexes I to IV. Increased activity of transcription factors such as myc and HIF-1α coordinates with the loss of tumor suppressive function of p53. A loss of function of p53 correlates with the increase of Glut transporters (transcription and surface translocation) via NF-κB. In addition, mitochondrial biogenesis promoted by myc results in the overproduction of ROS. ROS can cause mtDNA spontaneous mutations, rendering mitochondrial enzymes dysfunctional and, thus, OxPhos, leaving only aerobic glycolysis, a probable mode of energy production in transformed cells.
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