scholarly journals Amino Acid Transport and Metabolism in Myeloid Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Marie Jo Halaby ◽  
Tracy L. McGaha
Keyword(s):  
Amino Acid ◽  
Immune Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Amino Acid Transporters ◽  
Microbial Infection ◽  
Amino Acid Availability ◽  
Recent Developments ◽  
Functional Polarization ◽  
The Impact

Regulation of amino acid availability and metabolism in immune cells is essential for immune system homeostasis and responses to exogenous and endogenous challenges including microbial infection, tumorigenesis and autoimmunity. In myeloid cells the consumption of amino acids such as arginine and tryptophan and availability of their metabolites are key drivers of cellular identity impacting development, functional polarization to an inflammatory or regulatory phenotype, and interaction with other immune cells. In this review, we discuss recent developments and emerging concepts in our understanding of the impact amino acid availability and consumption has on cellular phenotype focusing on two key myeloid cell populations, macrophages and myeloid derived suppressor cells (MDSCs). We also highlight the potential of myeloid-specific of amino acid transporters and catabolic enzymes as immunotherapy targets in a variety of conditions such as cancer and autoimmune disease discussing the opportunities and limitations in targeting these pathways for clinical therapy.

scholarly journals Modeling of excitatory amino acid transporters and clearance of synaptic cleft on millisecond time scale

2019 ◽  
Vol 14 (4) ◽  
pp. 407
Author(s):  
Denis Shchepakin ◽  
Leonid Kalachev ◽  
Michael Kavanaugh
Keyword(s):  
Amino Acid ◽  
Time Scale ◽  
Time Course ◽  
Transport Model ◽  
Excitatory Amino Acid ◽  
Synaptic Cleft ◽  
Amino Acid Transporters ◽  
Excitatory Amino Acid Transporters ◽  
Millisecond Time Scale ◽  
The Impact

Excitatory Amino Acid Transporters (EAATs) operate over wide time scales in the brain. They maintain low ambient concentrations of the primary excitatory amino acid neurotransmitter glutamate, but they also seem to play a significant role in clearing glutamate from the synaptic cleft in the millisecond time-scale process of chemical communication that occurs between neurons. The detailed kinetic mechanisms underlying glutamate uptake and clearance remain incompletely understood. In this work we used a combination of methods to model EAAT kinetics and gain insight into the impact of transport on glutamate dynamics in a general sense. We derive reliable estimates of the turnover rates of the three major EAAT subtypes expressed in the mammalian cerebral cortex. Previous studies have provided transporter kinetic estimates that vary over an order of magnitude. The values obtained in this study are consistent with estimates that suggest the unitary transporter rates are approximately 20-fold slower than the time course of glutamate in the synapse. A combined diffusion/transport model provides a possible mechanism for the apparent discrepancy.

scholarly journals The glycation level of milk protein strongly modulates post-prandial lysine availability in humans

2019 ◽  
Vol 123 (5) ◽  
pp. 545-552 ◽  
Author(s):  
Jean Nyakayiru ◽  
Glenn A. A. van Lieshout ◽  
Jorn Trommelen ◽  
Janneau van Kranenburg ◽  
Lex B. Verdijk ◽  
...  
Keyword(s):  
Amino Acid ◽  
Milk Protein ◽  
Milk Proteins ◽  
Ultra Performance Liquid Chromatography ◽  
Protein Glycation ◽  
Plasma Amino Acid ◽  
Amino Acid Availability ◽  
Protein Ingestion ◽  
The Impact ◽  
Amino Acid Concentrations

AbstractIndustrial heat treatment of milk results in protein glycation. A high protein glycation level has been suggested to compromise the post-prandial rise in plasma amino acid availability following protein ingestion. In the present study, we assessed the impact of glycation level of milk protein on post-prandial plasma amino acid responses in humans. Fifteen healthy, young men (age 26 (SEM 1) years, BMI 24 (SEM 1) kg/m2) participated in this randomised cross-over study and ingested milk protein powder with protein glycation levels of 3, 20 and 50 % blocked lysine. On each trial day, arterialised blood samples were collected at regular intervals during a 6-h post-prandial period to assess plasma amino acid concentrations using ultra-performance liquid chromatography. Plasma essential amino acid (EAA) concentrations increased following milk protein ingestion, with the 20 and 50 % glycated milk proteins showing lower overall EAA responses compared with the 3 % glycated milk protein (161 (SEM 7) and 142 (SEM 7) v. 178 (SEM 9) mmol/l × 6 h, respectively; P ≤ 0·011). The lower post-prandial plasma amino acid responses were fully attributed to an attenuated post-prandial rise in circulating plasma lysine concentrations. Plasma lysine responses (incremental AUC) following ingestion of the 20 and 50 % glycated milk proteins were 35 (SEM 4) and 92 (SEM 2) % lower compared with the 3 % glycated milk protein (21·3 (SEM 1·4) and 2·8 (SEM 0·7) v. 33·3 (SEM 1·7) mmol/l × 6 h, respectively; P < 0·001). Milk protein glycation lowers post-prandial plasma lysine availability in humans. The lower post-prandial availability of lysine following ingestion of proteins with a high glycation level may compromise the anabolic properties of a protein source.

Regulation of amino acid transporters by amino acid availability

2001 ◽  
Vol 4 (5) ◽  
pp. 425-431 ◽  
Author(s):  
Graham R. Christie ◽  
Russell Hyde ◽  
Harinder S. Hundal
Keyword(s):  
Amino Acid ◽  
Amino Acid Transporters ◽  
Amino Acid Availability

scholarly journals Modulation of Immunity by Antiangiogenic Molecules in Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Magali Terme ◽  
Orianne Colussi ◽  
Elie Marcheteau ◽  
Corinne Tanchot ◽  
Eric Tartour ◽  
...  
Keyword(s):  
Immune Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Immunomodulatory Effects ◽  
New Class ◽  
Immune Parameters ◽  
Therapeutic Drugs ◽  
The Impact ◽  
Immunosuppressive Cytokines ◽  
Potential Biomarkers

In the last decades a new class of therapeutic drugs have been developed that block tumor angiogenesis. These antiangiogenic molecules, which target VEGF or VEGFR, PDGFR, and c-kit, can act not only on endothelial cells but also on immune cells. Some antiangiogenic molecules inhibit the development of immunosuppressive mechanisms developed by the tumors to escape the immune system (such as regulatory T cells, myeloid-derived suppressor cells, and immunosuppressive cytokines). These immunomodulatory effects must be characterized in detail to enable a better prescription of these treatments. In this paper we will focus on the impact of anti-angiogenic drugs on immunosuppression and their potential combination with immunotherapeutic strategies. Interestingly, immune parameters or their modulation during treatment could serve as potential biomarkers of response or resistance to anti-angiogenic therapies.

scholarly journals Quantitative analysis of how Myc controls T cell proteomes and metabolic pathways during T cell activation

2019 ◽  
Author(s):  
Julia M. Marchingo ◽  
Linda V. Sinclair ◽  
Andrew J. M. Howden ◽  
Doreen A. Cantrell
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Activation ◽  
Cell Activation ◽  
Amino Acid Transporters ◽  
Activated T Cells ◽  
Factor C ◽  
The Impact

SummaryT cell expansion and differentiation are critically dependent on the transcription factor c-Myc (Myc). Herein we use quantitative mass-spectrometry to reveal how Myc controls antigen receptor driven cell growth and proteome restructuring in T cells. Analysis of copy numbers per cell of >7000 proteins provides new understanding of the selective role of Myc in controlling the protein machinery that govern T cell fate. The data identify both Myc dependent and independent metabolic processes in immune activated T cells. We uncover that a primary function of Myc is to control expression of multiple amino acid transporters and that loss of a single Myc-controlled amino acid transporter effectively phenocopies the impact of Myc deletion. This study provides a comprehensive map of how Myc selectively shapes T cell phenotypes, revealing that Myc induction of amino acid transport is pivotal for subsequent bioenergetic and biosynthetic programs and licences T cell receptor driven proteome reprogramming.

scholarly journals Lysosomal amino acid transporters as key players in inflammatory diseases

2021 ◽  
Author(s):  
Noriko Toyama-Sorimachi ◽  
Toshihiko Kobayashi
Keyword(s):  
Signal Transduction ◽  
Amino Acid ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Metabolic Adaptation ◽  
Amino Acid Transporters ◽  
Proof Of Concept ◽  
Immune Mediated ◽  
Solute Carrier

Abstract Controlling inflammation can alleviate immune-mediated, lifestyle-related and neurodegenerative diseases. The endolysosome system plays critical roles in inflammatory responses. Endolysosomes function as signal transduction hubs to convert various environmental danger signals into gene expression, enabling metabolic adaptation of immune cells and efficient orchestration of inflammation. Solute carrier family 15 member 3 (SLC15A3) and member 4 (SLC15A4) are endolysosome-resident amino acid transporters that are preferentially expressed in immune cells. These transporters play essential roles in signal transduction through endolysosomes, and the loss of either transporter can alleviate multiple inflammatory diseases because of perturbed endolysosome-dependent signaling events, including inflammatory and metabolic signaling. Here, we summarize the findings leading to a proof-of-concept for anti-inflammatory strategies based on targeting SLC15 transporters.

scholarly journals Amino acid transceptors: gate keepers of nutrient exchange and regulators of nutrient signaling

2009 ◽  
Vol 296 (4) ◽  
pp. E603-E613 ◽  
Author(s):  
Harinder S. Hundal ◽  
Peter M. Taylor
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Dual Function ◽  
Amino Acid Transporters ◽  
Coupled Transport ◽  
Extracellular Milieu ◽  
Mammalian Cell Lines ◽  
Amino Acid Availability ◽  
Intracellular Amino Acid ◽  
Extracellular Amino Acid

Amino acid transporters at the surface of cells are in an ideal location to relay nutritional information, as well as nutrients themselves, to the cell interior. These transporters are able to modulate signaling downstream of intracellular amino acid receptors by regulating intracellular amino acid concentrations through processes of coupled transport. The concept of dual-function amino acid transporter/receptor (or “transceptor”) proteins is well established in primitive eukaryotes such as yeast, where detection of extracellular amino acid deficiency leads to upregulation of proteins involved in biosynthesis and transport of the deficient amino acid(s). The evolution of the “extracellular milieu” and nutrient-regulated endocrine controls in higher eukaryotes, alongside their frequent inability to synthesize all proteinaceous amino acids (and, hence, the requirement for indispensable amino acids in their diet), appears to have lessened the priority of extracellular amino acid sensing as a stimulus for metabolic signals. Nevertheless, recent studies of amino acid transporters in flies and mammalian cell lines have revealed perhaps unanticipated “echoes” of these transceptor functions, which are revealed by cellular stresses (notably starvation) or gene modification/silencing. APC-transporter superfamily members, including slimfast, path, and SNAT2 all appear capable of sensing and signaling amino acid availability to the target of rapamycin (TOR) pathway, possibly through PI 3-kinase-dependent mechanisms. We hypothesize (by extrapolation from knowledge of the yeast Ssy1 transceptor) that, at least for SNAT2, the transceptor discriminates between extracellular and intracellular amino acid stimuli when evoking a signal.

scholarly journals Effect of 30 % nutrient restriction in the first half of gestation on maternal and fetal baboon serum amino acid concentrations

2012 ◽  
Vol 109 (8) ◽  
pp. 1382-1388 ◽  
Author(s):  
Thomas J. McDonald ◽  
Guoyao Wu ◽  
Mark J. Nijland ◽  
Susan L. Jenkins ◽  
Peter W. Nathanielsz ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Maternal Blood ◽  
Nutrient Restriction ◽  
Adult Disease ◽  
Amino Acid Availability ◽  
Lower Body Weight ◽  
Uterine Growth ◽  
The Impact ◽  
Amino Acid Concentrations

Mechanisms linking maternal nutrient restriction (MNR) to intra-uterine growth restriction (IUGR) and programming of adult disease remain to be established. The impact of controlled MNR on maternal and fetal amino acid metabolism has not been studied in non-human primates. We hypothesised that MNR in pregnant baboons decreases fetal amino acid availability by mid-gestation. We determined maternal and fetal circulating amino acid concentrations at 90 d gestation (90dG, term 184dG) in control baboons fed ad libitum (C, n 8) or 70 % of C (MNR, n 6). Before pregnancy, C and MNR body weights and circulating amino acids were similar. At 90dG, MNR mothers had lower body weight than C mothers (P< 0·05). Fetal and placental weights were similar between the groups. MNR reduced maternal blood urea N (BUN), fetal BUN and fetal BUN:creatinine. Except for histidine and lysine in the C and MNR groups and glutamine in the MNR group, circulating concentrations of all amino acids were lower at 90dG compared with pre-pregnancy. Maternal circulating amino acids at 90dG were similar in the MNR and C groups. In contrast, MNR fetal β-alanine, glycine and taurine all increased. In conclusion, maternal circulating amino acids were maintained at normal levels and fetal amino acid availability was not impaired in response to 30 % global MNR in pregnant baboons. However, MNR weight gain was reduced, suggesting adaptation in maternal–fetal resource allocation in an attempt to maintain normal fetal growth. We speculate that these adaptive mechanisms may fail later in gestation when fetal nutrient demands increase rapidly, resulting in IUGR.

scholarly journals Amino acid transporters: roles in amino acid sensing and signalling in animal cells

2003 ◽  
Vol 373 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Russell HYDE ◽  
Peter M. TAYLOR ◽  
Harinder S. HUNDAL
Keyword(s):  
Gene Expression ◽  
Amino Acids ◽  
Amino Acid ◽  
Nutrient Availability ◽  
Cellular Response ◽  
Amino Acid Transporters ◽  
Animal Cells ◽  
Amino Acid Availability ◽  
Altered Gene ◽  
Amino Acid Sensing

Amino acid availability regulates cellular physiology by modulating gene expression and signal transduction pathways. However, although the signalling intermediates between nutrient availability and altered gene expression have become increasingly well documented, how eukaryotic cells sense the presence of either a nutritionally rich or deprived medium is still uncertain. From recent studies it appears that the intracellular amino acid pool size is particularly important in regulating translational effectors, thus, regulated transport of amino acids across the plasma membrane represents a means by which the cellular response to amino acids could be controlled. Furthermore, evidence from studies with transportable amino acid analogues has demonstrated that flux through amino acid transporters may act as an initiator of nutritional signalling. This evidence, coupled with the substrate selectivity and sensitivity to nutrient availability classically associated with amino acid transporters, plus the recent discovery of transporter-associated signalling proteins, demonstrates a potential role for nutrient transporters as initiators of cellular nutrient signalling. Here, we review the evidence supporting the idea that distinct amino acid “receptors” function to detect and transmit certain nutrient stimuli in higher eukaryotes. In particular, we focus on the role that amino acid transporters may play in the sensing of amino acid levels, both directly as initiators of nutrient signalling and indirectly as regulators of external amino acid access to intracellular receptor/signalling mechanisms.

scholarly journals Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors

2019 ◽  
Vol 20 (14) ◽  
pp. 3426 ◽  
Author(s):  
Stacey A Krepel ◽  
Ji Ming Wang
Keyword(s):  
G Protein ◽  
Cancer Progression ◽  
Inflammatory Responses ◽  
Myeloid Cell ◽  
Cell Types ◽  
Cell Trafficking ◽  
Microbial Infection ◽  
Physiological Processes ◽  
Recent Developments ◽  
G Protein Coupled

Leukocyte infiltration is a hallmark of inflammatory responses. This process depends on the bacterial and host tissue-derived chemotactic factors interacting with G-protein-coupled seven-transmembrane receptors (GPCRs) expressed on the cell surface. Formylpeptide receptors (FPRs in human and Fprs in mice) belong to the family of chemoattractant GPCRs that are critical mediators of myeloid cell trafficking in microbial infection, inflammation, immune responses and cancer progression. Both murine Fprs and human FPRs participate in many patho-physiological processes due to their expression on a variety of cell types in addition to myeloid cells. FPR contribution to numerous pathologies is in part due to its capacity to interact with a plethora of structurally diverse chemotactic ligands. One of the murine Fpr members, Fpr2, and its endogenous agonist peptide, Cathelicidin-related antimicrobial peptide (CRAMP), control normal mouse colon epithelial growth, repair and protection against inflammation-associated tumorigenesis. Recent developments in FPR (Fpr) and ligand studies have greatly expanded the scope of these receptors and ligands in host homeostasis and disease conditions, therefore helping to establish these molecules as potential targets for therapeutic intervention.

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