TYPE Review PUBLISHED 20 October 2022 DOI 10.3389/fimmu.2022.984408 Solute carrier nutrient OPEN ACCESS transporters in rheumatoid EDITED BY Andras Perl, Upstate Medical University, arthritis fibroblast- United States REVIEWED BY like synoviocytes Carmen Conde, Hospital Clinico de Santiago, Spain Ganesan Ramamoorthi, Alyssa Torres 1, Brian Pedersen 1,2 and Monica Guma 1,2,3* Moffitt Cancer Center, United States 1 Division of Rheumatology, Allergy and Immunology and School of Medicine, University of *CORRESPONDENCE California, San Diego, San Diego, CA, United States, 2 Department of Medicine, Veterans' Affairs (VA) Monica Guma San Diego Healthcare System, San Diego, CA, United States, 3 Department of Medicine, mguma@health.ucsd.edu Autonomous University of Barcelona, Barcelona, Spain SPECIALTY SECTION This article was submitted to Autoimmune and Autoinflammatory Disorders, Metabolomic studies show that rheumatoid arthritis (RA) is associated with a section of the journal Frontiers in Immunology metabolic disruption. Metabolic changes in fibroblast-like synoviocytes (FLS) RECEIVED 02 July 2022 likely contribute to FLS abnormal response and strongly contribute to joint ACCEPTED 26 September 2022 destruction. These changes often involve increased expression of nutrient PUBLISHED 20 October 2022 transporters to meet a high demand for energy or biomolecules. The solute CITATION carrier (SLC) transporter families are nutrient transporters and serve as Torres A, Pedersen B and Guma M ‘metabolic gates’ for cells by mediating the transport of several different (2022) Solute carrier nutrient transporters in rheumatoid arthritis nutrients such as glucose, amino acids, vitamins, neurotransmitters, and fibroblast-like synoviocytes. inorganic/metal ions. In RA FLS SLC-mediated transmembrane transport was Front. Immunol. 13:984408. doi: 10.3389/fimmu.2022.984408 one pathway associated with different epigenetic landscape between RA and osteoarthritis (OA) FLS. These highlight that transporters from the SLC family COPYRIGHT © 2022 Torres, Pedersen and Guma. offer unique targets for further research and offer the promise of future This is an open-access article therapeutic targets for RA. distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or KEYWORDS reproduction in other forums is SLC transporters, FLS, RA, metabolism, nutrients permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Introduction Rheumatoid arthritis (RA) is a complex autoimmune disease that classically affects the small joints of the hands and feet. Its pathogenesis is driven by an interplay between cells of the immune system and the cells comprising the tissues of a joint (1, 2). This includes T cells, B cells, macrophages, chondrocytes and fibroblast-like synoviocytes (FLS). The FLS in a joint affected by RA, are a key driver of the inflammatory response that leads to damage and loss of a structural integrity of the affected joint (3, 4). These FLS play a role in the dysregulation of the innate and adaptive immune response and increasing evidence demonstrate the multifaceted ways in which metabolic changes are involved in the pathogenesis of RA and abnormal RA FLS behaviour (5–7). Frontiers in Immunology 01 frontiersin.org Torres et al. 10.3389/fimmu.2022.984408 The SLC (solute carrier) gene superfamily current consists of on signaling, differentiation, and cell function by manipulating 458 protein-coding genes with 65 distinct gene families (8). Genes metabolite concentrations from normal levels, as seen in within a family are grouped based only on the primary amino acid immune cells (26). For these reasons, SLC transporters have sequence. By definition, members of a family have >20-25% DNA been explored as treatment targets for some conditions and sequence homology to one another. In vitro studies and animal diseases (27). models have demonstrated key functions of these transporters for basic nutrients and ions, energy metabolism, neurotransmission, and xenobiotic/drug transport (8, 9). SLC1 glutamate and neutral amino Not unexpectedly, SLC transporters are important in normal acid transporter family health and disease states (9, 10) This is evidenced by greater than half of SLC transporters being associated with either The plasma membrane transporters for the neurotransmitter susceptibility to a human disease or directly attributable to a glutamate belong to the solute carrier 1 (SLC1) family (28). Mendelian human disease (11). This includes diseases affecting Other common names of these transporters include Excitatory the immune system, cardiovascular disease, metabolic disease, Amino-Acid Carrier 1 (EAAC1 or SLC1A1), Glutamate neurological functioning and cancer. In comparison, ~20% of Transporter (GLT1 or SLC1A2), Glutamate Aspartate genes in general are known to be associated with human disease. Transporter 1 (GLAST or SLC1A3), Excitatory Amino We recently described that in RA FLS, changes in the acid Transporter 4 (EAAT4 or SLC1A6), and Excitatory epigenetic landscape of genes are related to nutrient transporters, Amino Acid Transporter 5 (EAAT5 or SLC1A7), to name a revealing a potential role of the SLC family in RA pathogenesis few. Glutamate transporters are of particular importance in the (12). In addition, several papers described associations of SLC brain, where they contribute to the termination of excitatory transporter polymorphisms with RA (13–18). In this review, we neurotransmission, but they are also expressed in many tissues. concentrate on the roles of SLC transporters on the pathogenesis of Constitutive expression of EAAC1 (SLC1A1), GLAST RA. We focus our review on studies of SLCs in RA FLS as they are (SLC1A3), and GLT1 (SLC1A2) mRNA was shown in synovial critical in regulating cell metabolism and are involved in the tissue and confirmed by immunohistochemical (IHC) analysis pathogenesis of RA (Figure 1). (29, 30). Levels of glutamate increased in arthritis paws in a rat animal model of arthritis. When testing the effect of glutamate on increased proliferation positively correlated with higher Importance of metabolic regulation concentrations of glutamate for RA rat fibroblast in comparison on RA pathogenesis and SLC roles in to normal rat fibroblasts. When given the non-selective EAAT metabolism regulation inhibitors L-threo-B-hydroxyaspartate and carboxycyclopropyl) glycine (CCG-III), but nor GLT1 inhibitors, decrease glutamate Several studies have been conducted on the role of accumulation and proliferation was significantly decreased despite metabolism in RA pathogenesis. Different cell types in the higher levels of glutamate (31). These results imply a relatively inflamed synovium require various metabolites in order to selective dependence upon EAAT transporters to deliver meet energy demands including lactate, citrate, and succinate glutamate for the metabolic needs of proliferating RA fibroblasts. (5, 19, 20). This metabolic change is also accompanied by differences in immunity and inflammation and affects both stromal and immune cells (21). The result of these changes SLC2 glut transporter family has also been described and explored by different groups and involves such pathways as glycolysis, pentose phosphate All fourteen members of the SLC2 family encode GLUT pathway, and biosynthetic activity (22). It is suggested that proteins. The SLC2 or GLUT family are uniporters of hexoses, rewiring of the RA synovial membrane could modulate disease polyols and yet to be determined substrates and mediate the first activity as has been shown in tumor cells and cancer (23). Some step for cellular glucose usage (32). Deregulated glucose studies on metabolism and RA have focused on RA FLS in this metabolism of tumor and non-tumor cells is known to affect inflammatory state, including specific pathways such as glucose cell behavior. RA FLS were found to have more glycolysis activity metabolism, phospholipid metabolism, and bioactive lipids than OA FLS by our group and others (33, 34). SLC2A1 (also which differ from healthy synovial fibroblasts (24). known as GLUT1) typically plays a role in basal glucose uptake. SLC transporters have been shown to be important in Interestingly, GLUT1 increased mRNA expression of RA FLS different physiological functions, but have also been studied specifically correlated with increased glycolysis. Additionally, for the effect of their expression on metabolite concentration inhibitors of glycolysis, like 2DG and bromopyruvate, or glucose in cells, and their involvement in various diseases (25). Some of deprivation decreases proliferation and migration of RA FLS. these roles SLC transporters have on disease activity are effects The expression of GLUT1 mRNA in the synovial lining has been Frontiers in Immunology 02 frontiersin.org Torres et al. 10.3389/fimmu.2022.984408 FIGURE 1 Depiction of the localization and solutes transported by the SLC transporter genes associated with RA FLS aggressive phenotype. SLC, solute carrier; Glu, glutamate; Asp, aspartate; Ala, alanine; Asn, asparagine; Cys, cysteine; His, histidine; Ser, Serine; Zn, zinc; Cd, Cadmium; Mn, Magnesium; T3, Triiodothyronine; T4, Thyroxine; L-DOPA, L-Dopamine; AA, amino acids; BCH, 2-aminobicyclo-(2, 2, 1)-heptane-2-carboxylic acid. confirmed in a mouse model of inflammatory arthritis and SLC4 bicarbonate transporter family glycolysis inhibition through BrPa (3-Bromo pyruvate) decreased arthritis severity in this model (33). Overexpression The SLC4 family members transport bicarbonate and consist of hexokinase 2, which is specifically expressed in RA synovial of 10 genes that play roles in acid-base homeostasis (40). In lining and regulates FLS aggressive functions, also increased addition to regulating pH, bicarbonate transporters contributes GLUT1 mRNA levels (35). Increased GLUT-1 and decreased to a cell’s ability to fine tune the intracellular regulation of the GLUT-4 (SLC2A4) expression in RA synovium compared to OA cotransported/exchanged ion(s) (e.g., Na+ or Cl−) (41). In the synovium was confirmed for other groups (36). Of interest, TNF context of these transporters playing a known role in migration stimulation enhanced GLUT1 expression in RA FLS (37). of other cell types, one group has investigated the role of Another study looked at the effect of D-lactate and its bicarbonate transporters on RA FLS migrations. Upon testing relationship with GLUT1. The physiological concentration of various genes of the SLC4 family, SLC4A7 (also known as lactate in normal tissues is about 1.5–3 mmol/L but can increase NBCn1) was shown to be significantly increased in RA FLS to 10–12 mmol/L at sites of inflammation such as rheumatic upon TNF-a expression as compared to OA FLS (42). As a result, synovial fluid. When RA FLS were stimulated with D-lactate for TNF stimulation significantly increased migration. NBCn1 was six hours, GLUT1 mRNA, amongst other genes, was also found to be in the plasma membrane after TNF stimulation. significantly increased through HIF1a, PI3K/Akt and NF-kB Upon the use of NBC inhibitor S0859, RA FLS migration was signaling pathways (38). Finally, another group studied the attenuated. As bicarbonate affects pH and RA patients tend to involvement of T lymphocytes in RA FLS by giving T cell have more acidic synovial fluid, they tested the effect of pH on conditioned media to RA FLS or culturing the FLS with CD4 FLS migration and found that more acidic conditions increased T cells (39). CD4 conditioned media caused increased glycolysis RA-FLS migration and NBCn1 expression. An NBC inhibitor, in FLS and downregulated oxidative phosphorylation which was S0859, decreased RA FLS migration and reduce bone erosion paralleled by increased both GLUT1 and GLUT3 mRNA. The and edema in joints in the collagen induced arthritis (CIA) above studies suggest that targeted changes in the activity of model (42). SLC2 family members could be exploited as adjunct therapeutic Similar to the findings of M. Ji et. al., our group also found targets for RA. SLC4A4 (NBCe1) expression to be increased in OA vs RA FLS Frontiers in Immunology 03 frontiersin.org Torres et al. 10.3389/fimmu.2022.984408 (12, 42). Upon siRNA knockdown of SLC4A4, RA FLS were This study found that ferroptosis resistance in FLS was regulated found to be more invasive but with unchanged migration by TNF by upregulating SLC7A11, glutamate-cysteine ligase compared to control siRNA (12). This collection of findings catalytic subunit (GCLM), and glutamate-cysteine ligase demonstrates the potential direct role of the SLC4 bicarbonate regulatory subunit (GCLC) and increasing cysteine uptake. A transporters in regulating the pH of pathologic synovium and TNF antagonist allowed RA FLS to become more susceptible to their role in RA disease progression. ferroptosis, so the combination of a TNF antagonist and a ferroptosis inducer had a synergistic effect in RA FLS but not in healthy synoviocytes (50). A similar approach also described SLC7 cationic amino acid that ferroptosis is decreased in RA FLS by looking at transporter/glycoprotein mitochondrial morphology and membrane potential in RA FLS along with increases in SLC7A11 (51). They also looked at associated family the effect of glycine on ferroptosis (51) Glycine enhanced ferroptosis by increasing GPX4 promoter methylation, which The SLC7 family transports amino acids, particularly, decrease dGPX4 expression, and by increasing the expression of SLC7A5 also known as LAT1, transports large, neutral, L-type ferritin heavy chain 1 (FTH1), which releases iron and induces amino acids (43). Amino acids play essential roles in cell biology ferroptosis. In addition, glycine reduced progression of as regulators of metabolic pathways. In RA FLS, the heterodimer ferroptosis in the CIA mouse model. The above studies of SLC3A2 and SLC7A5 mediates cellular uptake of large neutral suggest that the modulation of ferroptosis, as shown with amino acids like phenylalanine (39), tyrosine, leucine, and sulfasalazine (52), by targeting SLC7A11 among other tryptophan (28). SLC7A5 is overexpressed in RA synovial strategies can be exploited as adjunct therapeutic targets for RA. tissue as compared with OA synovial tissue, and found to colocalize with FLS through immunofluorescence of synovial tissue from RA patients (44). This group also found that IL1b stimulation upregulated SLC7A5 and induced mTORC1 SLC16 monocarboxylate activation. Another group utilized RNAi and the LAT1 transporter family inhibitor, L-leucine analogue b(−)2-aminobicyclo[2,2, 1] heptane-2-carbocyclic acid (BCH), to test the effect on The SLC16 family (specifically SLC16A1, SLC16A3, SLC16A7, downstream mechanisms (45). Both methods resulted in and SLC16A8) transports monocarboxylates such as l-lactate, reduced phosphorylation of mTOR and 4EBP1, leucine uptake pyruvate, and ketone bodies across the plasma membrane (53). and migration in RA FLS. Interestingly, IL-17 increased SLC16A2 is specifically involved in transporting thyroid expression of SLC7A5, which was attenuated by inhibiting the hormones, while the other nine transporters are involved in mTOR pathway (45). transporting other molecules or their role is otherwise known. SLC7A11 is a transporter that is targeted by the RA drug SLC16A3, also known as monocarboxylate transporter 4 sulfasalazine and is also referred to as xCT or system XC-. This (MCT4), is known to transport lactate and ketone bodies. transporter specifically exports glutamate and imports cysteine. SLC16A3 mRNA and protein expression is upregulated in RA Cysteine is essential for glutathione synthesis which has effects in compared to OA FLS and exports intracellular lactate into the ferroptosis and reactive oxygen species resistance (46). One extracellular space (54). MCT4 siRNA reduced RA FLS study investigated the effect of icariin (47), shown to promote proliferation in comparison to OA FLS. This effect was anticancer, antiaging, neuroprotective, and anti-inflammatory mediated by increased apoptosis. In an in vivo mouse model effects, on ferroptosis in FLS (48). FLS stimulated by of collagen induced arthritis (CIA), MCT4 siRNA was lipopolysaccharide (LPS) were used as a synovitis cell model. electroporated into the joint tissue of mice, decreased MCT4 ICA inhibited cell death, increased cell viability, reduced lipid levels and was associated with reduced synovial cell hyperplasia peroxidation, reduced iron content, and inhibited ferroptosis- and infiltration. However, no difference in severity of cartilage related proteins as compared to controls. ICA inhibited destruction and bone erosion was observed. ferroptosis by activating the XC-system and glutathione peroxidase 4 (GPX4) activity, suggesting a role of ferroptosis in FLS aggressive phenotype. Of interest, a recent study used an opposing approach and SLC30 zinc efflux family and SLC39 used imidazole ketone erastin (49), which is a ferroptosis metal ion transporter family inducer, to decrease fibroblast numbers in synovium accompanied by a TNF antagonist, to halt progression of Zinc ions are essential in many physiological processes, including arthritis in the collagen-induced arthritis (CIA) mouse model. enzyme catalysis, protein structural stabilization, and the regulation Frontiers in Immunology 04 frontiersin.org Torres et al. 10.3389/fimmu.2022.984408 of many proteins, including matrix metalloproteinases (MMPs), a ferroptosis upon sensitization with IL-6. They found that IL-6 disintegrin and metalloproteinase (ADAM), and a disintegrin decreased expression of SLC40A1 and lowered ferritin. Upon and metalloproteinase with thrombospondin motif (ADAMTS) knockdown of SLC40A1, RSL3-driven ferroptosis toxicity was (55, 56). These proteases play key roles in the formation, increased. Based on these findings, IL-6 caused an increase in homeostasis and remodeling of the extracellular matrix and the intracellular iron levels which could contribute to RA FLS cartilage. The SLC30 family are specifically exporters of zinc and are proliferation. Of note, increased intracellular iron levels commonly referred to as Zinc transporters (ZnTs). In contrast, the positive correlates with tumor growth (33). SLC39 family are importers of zinc and are commonly referred to as Zrt- and Irt-like proteins (ZIPs), but can also transport a handful of other metals. In FLS, it has been found that upon TNF and IL-17 stimulations, zinc exporters (SLC30) and importers (SLC39), there SLC44 choline-like are variable effects on Zinc exporters (SLC30) and importers. With transporter family this cytokine combination, SLC39A8 (also known as ZIP-8) expression significantly increased in RA FLS. However, in OA FLS, The SLC44 family comprises several high affinity choline only TNF was able to increase ZIP-8 expression, and no difference carriers which are thought to provide choline for phospholipid was observed when IL-17 was added. With increased amounts of and acetylcholine synthesis (60). Choline kinase (ChoKa), an Zinc, ZIP-8 expression was inhibited in RA FLS after TNF and IL-17 essential enzyme for phosphatidylcholine biosynthesis, is stimulation, but not in OA FLS. In contrast, SLC30A1 (also known as required for cell proliferation and has been implicated in ZnT1) expression was unchanged upon stimulation with TNF and cancer invasiveness. The relevance of choline, choline kinase IL-17, and expression was slightly enhanced with increased amounts and phosphocholine in RA FLS aggressive phenotype and of zinc, but upon the combination of zinc and cytokines, ZnT1 macrophage activation was described by our group and others expression was significantly increased. This combination of cytokines (31, 61, 62). SLC44A1 (also known as CTL1) is expressed widely and zinc also significantly increased IL-6 production in RA FLS (57). in the nervous system while the others, including SLC44A2 (also known as CTL2) are expressed in peripheral tissues. SLC44A2 is thought to be involved in autoimmune hearing loss SLC38 system A and system N One group found all five of the CTL proteins present in synovial tissue and cartilage of human joints. CTL1 and 2 being sodium-coupled neutral amino acid the most prominently expressed, but without a difference transporter family between OA and RA FLS (63). CTL1 and CTL2 were found to localize to both macrophages and fibroblasts in SLC38 family is a set of genes that primarily transports immunohistochemical staining, with CTL1 being the most amino acids. Specifically, SLC38A1, or system N amino acid prominent in synovium and cartilage (64). Another study transporter 1 (SNAT1), is a sodium coupled amino acid found CTL1 and CTL2 mRNA and protein to be highly transporter that is shown to be upregulated in human liver expressed in RA FLS and localized to the plasma membrane. cancer cell lines (58). SLC38A1 was shown to have differential They found that CHT1, CTL4, CTL5, OCT1, and OCT2 mRNAs epigenetic markings between RA and OA FLS with higher were not expressed in RA FLS. CTL3 and OCT3 were expressed expression in RA FLS than in OA FLS. Upon siRNA at low levels and proposed that inhibition of these transporters knockdown, there was no difference in migration or invasion, promote apoptotic cell death (65). In RA FLS, the exposure to suggesting a s redundancy in amino acid transporters (12). the choline uptake inhibitor hemicholinium-3 (HC-3) in dose specific manner, decreased cell viability and increased caspase 3/ 7 activity; both of which are markers of apoptosis (65). SLC40 basolateral iron transporter family SLC47 multidrug and toxin The SLC40 family consists of only one SLC named extrusion family SLC40A1, which is also called MTP1 or IREG1, and codes for a protein named ferroportin-1 (FPN1). It is involved in the The SLC47 family is called the multidrug and toxin cellular efflux of iron (59). In the paper previously described for extrusion (MATE) family which comprises of SLC47A1 (or SLC7A11 (50), this group briefly analyzed expression of MATE1) and SLC47A2 (or MATE2). MATE1 and MATE2 are SLC40A1 and its role in RA FLS ferroptosis. In this model, RA H+/organic cation antiporters that secrete organic cations and FLS incubated with a TNF antagonist were more sensitive to are mostly expressed kidney and liver (66). Frontiers in Immunology 05 frontiersin.org Torres et al. 10.3389/fimmu.2022.984408 One study looked at the effect of tyrosine kinase inhibitors The role of SLC transporters in (TKIs) in RA FLS and the role of these membrane transporters (67). The tyrosine kinase inhibitor Imatinib was studied for other cells transport and accumulation and found that MATE1 had the SLC transporters in RA are relevant in more than just FLS. greatest affinity for Imatinib. This was confirmed after siRNA Other cell types critical in RA pathogenesis, including knockdown of MATE1 caused decreased uptake of Imatinib chondrocytes, CD4+ T cells, monocytes, endothelial cells and transport into RA FLS With increased activity of MATE1 neutrophils express SLC transporters and they play a role in their following PDGF stimulation, proliferation was inhibited by activated phenotype. Table 1 summarizes they key findings. imatinib given its ability to enter the cell. When cells were under disease relevant conditions such as a lower pH and cytokine stimulation, imatinib uptake decreased. Previous studies suggested a potentiation of the effect of imatinib under these disease relevant conditions. SLC transporters as A different study found MATE1 to be increased in OA as therapeutic targets opposed to RA. MATE1 was also determined to mediate transport of Tofacitinib, a blocker of the ATP-binding side of The SLC family offer unique targets for further research and Janus kinase (JAK) proteins and tyrosine kinase inhibitor, from offer the promise of future therapeutic targets for RA. RA FLS (68). The increased expression of MATE1 in OA allows Importantly, many SLC transporters are expressed on the cell tofacitinib to be exported out of the cell, while the lower activity surface and are therefore targetable by both small molecules and of MATE1 in RA does not allow tofacitinib to leave the cell, thus therapeutic antibodies. Modulation of these SLC can also affect allowing tofacitinib to undergo its intended effects. It is both the efficacy and toxicity of RA therapies as suggested by the suggested that tofacitinib is a more ideal drug since healthy association of polymorphism with methotrexate toxicity (77– cells would be able to export it through MATE1 and thus not 82). A comprehensive understanding of the function of these undergo JAK inhibition while RA FLS would not be able to transporters and the pathways in which they act will be critical export it due to lower MATE1 expression. for recognizing SLC that may be therapeutically targeted in RA. TABLE 1 The role of SLC transporters in RA cells other than FLS. SLC Gene Alias Substrates Cell type Findings Reference family SLC2 SLC2A1 GLUT1 DHA, glucose, Chondrocytes DHA transported via GLUT1 regulated by hypoxia (69) SLC2A2 GLUT2 galactose, mannose, glucosamine SLC5 SLC5A12 SMCT2 Short chain fatty CD4+ T cells Lactate regulates T-cell migration and regulates metabolism and (70), (47) acids inflammation SLC7 SLC7A5 LAT1 Large neutral AA Monocytes Glycolytic reprogramming through SLC7A5 in immune response (71) Macrophages SLC7 SLC7A11 XC- Cysteine, Endothelial cells Sulfasalazine inhibits fibroblast growth-factor induced chemotaxis of (72) glutamate endothelial cells SLC16 SLC16A1 MCT1 Lactate, pyruvate, T cells Lactate regulates T-cell migration and regulates metabolism and (70) ketone bodies inflammation SLC29 SLC29A1 ENT1 Nucleoside T cells in animal Decitabine therapy results in long-term remission of RA (72) model SLC29 SLC29A1 ENT1 Nucleoside Mixed synovial cells Dipyridamole is an ENT inhibitor. It did not affect cytokine release in RA (73) SLC29A2 ENT2 and OA cells SLC38 SLC38A1 SNAT1 Gln, Ala, Asp, Cys, Monocytes Glutamine uptake is regulated by SNAT and attenuated AIA (74) SLC38A2 SNAT2 His, Ser Neutrophils SLC38A3 SNAT4 AIA SLC39 SLC39A8 ZIP8 Zinc Macrophages Zinc regulated IL-1b (75) SLC63 SLC63A2 SPNS2 Sphingolipids CIA model SPNS2 deletion improved arthritis (76) CIA, collagen induced arthritis; AIA, antigen induced arthritis, AA, amino acids; GLUT, glucose transporter; SMCT2, sodium-coupled monocarboxylate transporters; LAT1, L-type amino acid transporter; MCT1, monocarboxylate transporter 1; ENT, Equilibrative nucleoside transporter; SNAT, Sodium-Coupled Neutral Amino Acid Transporter; ZIP, Zrt- and Irt-like proteins; SPNS2, Sphingolipid Transporter 2; DHA, Dehydroascorbate Frontiers in Immunology 06 frontiersin.org Torres et al. 10.3389/fimmu.2022.984408 Author contributions Conflict of interest AT, BP, MG have contributed to the literature review. 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