Amino Acid Transport and Metabolism During Homeostasis and Inflammation

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Background

Activation of the immune system is linked to the upregulation of anabolic pathways, which are critical for immune cells to survive, proliferate, and perform their effector functions. To fulfill their requirements of energy and protein synthesis, activated immune cells upregulate the expression of several solute carrier (SLC) proteins, including glucose and amino acid transporters. An increasing number of studies have shown how uptake and metabolism of Leucine, Glutamine, Arginine, and Serine among other amino acids, modulate the outcome of TCR-activated T cells, NK cells, γδT cells, dendritic cells, and macrophages. Thus, amino acid transporters, as well as the enzymes involved in amino acid metabolism, are becoming attractive targets for the therapeutic control of immune responses.

Besides their role as precursors in protein synthesis, amino acids regulate cell function by controlling intracellular signaling pathways, acting as precursors of important metabolites, and regulating protein function by posttranscriptional modification. The mammalian target of rapamycin complex 1 (mTORC1) is a protein kinase that acts as a master regulator of cell growth and metabolism and exerts a critical role in the control of immune responses. Although mTORC1 is regulated by a wide range of signals, its activity requires certain amino acids in the medium and the expression of different amino acids transporters in the membrane, including leucine, glutamine/serine, and arginine transporters as well as intracellular amino acid transporters.

Amino acids are also a source of metabolites that dictate immune cell functions. Arginine can be catabolized into ornithine and urea by arginase-1 (Arg1), or into nitric oxide (NO) and citrulline by inducible NO synthase (iNOS). The preferential metabolism of arginine into either pathway plays a key role in macrophage differentiation and activation. Glutamine can be used for nucleotide synthesis and energy production by the TCA cycle. Serine is required for immune cell proliferation by supporting purine biosynthesis. Finally, tryptophan is the precursor for the synthesis of serotonin, kynurenine and several ligands for aryl hydrocarbon receptor (AHR) transcription factor, thus modulating immune responses and especially tumor-associated immunity.

The mechanisms that regulate amino acid transport, metabolism, and amino acid sensing during inflammatory responses remain poorly understood. Whether different immune cell types or inflammatory conditions, including tumor immunity, are regulated by the uptake or exclusion of specific amino acids, or the preferential engagement of amino acid catabolic or anabolic pathways, has not been studied in deep. Moreover, the role of substrate competition for each amino acid transporter has not been assessed in immune responses. Considering that organisms employ multiple homeostatic mechanisms in vivo to maintain extracellular amino acid levels, it is critical to understand how amino acid metabolism impacts immunity in vivo. For this reason, further studies focusing on amino acid metabolism in acute and chronic inflammatory conditions are required.

In this Research Topic, we welcome authors to submit Original Research, Mini Reviews and Perspective articles focusing on:

1) Regulation of amino acid transporters and amino acid-mediated metabolic pathways to control adaptive and innate immune responses, including immunity against tumors.

2) Role of amino acid sensors and amino acid-derived metabolites in immune cell homeostasis and activation, not only associated with mTOR pathway.

3) Evaluation of modified diets controlling amino acid levels to regulate immune cell homeostasis and development of inflammatory response in vivo.

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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