Nutrient sensing, signal transduction and immune responses
Introduction
Most tissues are well vascularised and replete with nutrients and oxygen. Therefore, under normal homeostatic conditions circulating immune cells or those within tissue are adequately supplied with the fuels they require to maintain energy homeostasis and cellular processes. However, this is not always the case and certain microenvironments can be significantly less accommodating. At inflamed sites the influx of inflammatory cells such as neutrophils and monocytes increases nutrient consumption and can lead to low glucose availability and tissue hypoxia [1]. Neutrophils have low levels of mitochondrial respiration and few functional mitochondria and as a result have a high demand for glucose to fuel glycolytic energy production as well as to support other cellular processes and effector functions [2], [3], [4]. At sites of infection there is additional demand for nutrients caused by the infecting pathogen. Glucose is an important fuel for many pathogenic bacteria, including the common human pathogen Staphylococcus aureus, and glucose levels can drop during bacterial infection [5], [6]. Additionally, many virus’ have been shown to reprogram the cells they infect towards increased glucose uptake and glycolysis to facilitate viral replication [7], [8], [9], [10], [11]. The microenvironment within solid tumours can also be considerably metabolically restrictive for infiltrating immune cells. Tumour cells consume large amounts of glucose, and other nutrients such as glutamine, and as a result the tumour microenvironment can become depleted of nutrients [12], [13], [14], [15]. Additionally, tumour cells and tumour promoting immune cells such as myeloid derived suppressor cells express enzymes such as arginase and indoleamine-2,3-dioxygenase that consume arginine and tryptophan respectively [12], [16]. Solid tumours can also become hypoxic due to insufficient vascularisation [17]. As mentioned above, tissue hypoxia can be a feature of certain immune microenvironments and while this will not be discussed in detail herein, it is the subject of various other review articles [18], [19].
Metabolic syndrome, a health care crisis that is reaching epidemic levels world wide, is a clustering of conditions including central obesity, dyslipidaemia and hypertension that increases the risks of morbidities such as cancer and cardiovascular disease. Another feature of metabolic syndrome is altered immune function [20]. Fatty acids, cholesterol and cholesterol derivatives have all been proposed to have roles in controlling immune function and the dysregulated systemic levels of these molecules in patients with metabolic syndrome is likely to underpin the observed alterations in immune function [21]. The levels of molecules like oxysterols can also be altered in discrete immune microenvironments. For instance, tumour cells release oxysterols into the tumour microenvironment [22] and activated macrophages make large amounts of the oxysterol 25-hydroxycholestrerol (25HC) [23]. It is also clear that dietary and microbiome derived molecules such as short chain fatty acids have a role to play in the control of immune responses.
Therefore, many of the environments in which immune cells operate can have variable levels of important nutrients, including glucose, amino acids, fatty acids and cholesterol/oxysterols. These molecules are all important for cellular metabolism or as structural components of the cell, but importantly, these molecules can also directly impact upon immune signalling pathways to influence immune activation, differentiation and function. Indeed, there is a growing appreciation that nutrients are important cues that can shape immune responses. This review article will discuss the various nutrient sensing signalling pathways and the roles they play in regulating the function of immune cells.
Section snippets
Glucose and glutamine sensing
Glucose and glutamine are important fuels that feed into different parts of the ATP generating pathways of the cell, glycolysis and oxidative phosphorylation (OxPhos), but can also supply various biosynthetic pathways. The levels of these fuels can impact upon multiple signalling pathways that are integral to the control of immune responses.
Amino acid sensing
Amino acids are important for biosynthetic pathways in immune cells, including protein and nucleotide synthesis. Furthermore, they can also be directly metabolised to generate immunomodulatory molecules such as nitric oxide; arginine is a substrate for inducible nitric oxide synthase (iNOS). Thus, it is not surprising that immune cells, in particular lymphocytes, greatly increase amino acid uptake in response to immune stimulation. Amino acids of particular importance to lymphocytes include
Fatty acid sensing and immune function
Free fatty acids (FFA) are aliphatic chains of varying carbon length that can be saturated or unsaturated containing a carboxylic acid [86]. Free fatty acids can be obtained exogenously through diet, produced by the gut microbiome and can also be produced from breakdown of triacylglycerides in the liver and adipose tissue. While FFA can be used as a cellular fuel for generating ATP, they also act as ligands for several g protein coupled receptors (GPCR) [87]. Many immune cells types have been
Cholesterol and oxysterol sensing
Cholesterol is an important component of the plasma membrane that is involved in maintaining membrane integrity and fluidity, but cholesterol also has roles in signal transduction. There are multiple branches off the cholesterol biosynthesis pathway that generate intermediates important for steroid hormone production and protein prenylation, and in the regulation of immune responses [124]. Cholesterol can also be oxidised into various oxysterol molecules, such as 25HC, that are important in the
Final remarks
The phrase “you are what you eat” has been used for some time to convey the idea that ones diet, healthy or otherwise, has a big influence on ones wellbeing. It is now becoming clear that this phrase also resonates at the cellular level with respect to our immune cells. The identity of an immune cell, the pro and anti-inflammatory characteristics of immune cells, can be significantly influenced by the nutrients that are available to it in the local microenvironment. At the same time there is an
Conflicts of interest
The authors declare no competing financial interests.
Acknowledgements
David Finlay is supported by funding from Science Foundation Ireland (12/IP/1286 and 13/CDA/2161) and Marie Curie Actions (PCIG11-GA-2012-321603). Jessica Walls is supported by a Wellcome Trust Studentship (106811/Z/15/Z).
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