Metabolic Pathways That Control Skin Homeostasis and Inflammation

Trends in Molecular Medicine

Opinion Metabolic Pathways That Control Skin Homeostasis and Inﬂammation

Danay Cibrian,1,2 Hortensia de la Fuente,1,2 and Francisco Sánchez-Madrid1,2,*

Keratinocytes and skin immune cells are actively metabolizing nutrients present Highlights in their microenvironment. This is particularly important in common chronic Homeostatic skin requires low levels of inflammatory skin diseases such as psoriasis and atopic dermatitis, character- amino acids, promoting GCN2 and au- ized by hyperproliferation of keratinocytes and expansion of inflammatory tophagy pathways to maintain a balance between proliferation and differentiation. cells, thus suggesting increased cell nutritional requirements. Proliferating inflammatory cells and keratinocytes express high levels of glucose transporter Psoriasis and AD patients show in- (GLUT)1, L-type amino acid transporter (LAT)1, and cationic amino acid trans- creased levels of circulating amino acids porters (CATs). Main metabolic regulators such as hypoxia-inducible factor and metabolites of the glycolysis path- α way, underscoring that systemic meta- (HIF)-1 , MYC, and mechanistic target of rapamycin (mTOR) control immune bolic alteration can trigger or modulate cell activation, proliferation, and cytokine release. Here, we provide an updated disease onset or relapse. perspective regarding the potential role of nutrient transporters and metabolic pathways that could be common to immune cells and keratinocytes, to control Inhibition of GLUT1-mediated glucose uptake could be a novel strategy to con- psoriasis and atopic dermatitis. trol keratinocyte proliferation, with addi- tional immunoregulatory effects in the control of proinflammatory cytokines. Skin Homeostasis and Inflammation: Psoriasis and Atopic Dermatitis (AD) Dysregulation of the skin immune system and its barrier function underlies common chronic Blockade of LAT1 may represent a novel fl fl strategy to directly control in ammatory immunoin ammatory diseases such as psoriasis and AD [1]. Psoriasis is a common chronic cells in psoriasis and AD patients. inflammatory skin disease that affects 2–3% of the population worldwide. Clinically, psoriasis is characterized by well-delimited red, scaly plaques, and histologically, by increased Blocking mTOR directly or through the keratinocyte proliferation, dense dermal inflammatory infiltrates, and angiogenesis [2]. control of amino acid and energy supply αβ γδ is a novel strategy to control immune cell Psoriasis shows elevated levels of interleukin (IL)-23 and IL-17-releasing and T cells activation and keratinocyte dedifferentia- [3,4]. IL-22, a T helper (Th)17 cytokine, induces keratinocyte proliferation, antimicrobial peptide tion that are hallmarks of psoriasis and production, and neutrophil recruitment [5,6]. Tumor necrosis factor (TNF)α also contributes to AD diseases. psoriasis development through keratinocyte activation [7]. Therapy with blocking antibodies against TNFα, IL-17, or either subunit of IL-23 (p19 or p40) significantly ameliorates psoriatic lesions [8].

AD is the most common inflammatory skin disease, characterized by chronic eczema, pruritus, and high serum levels of IgE [9]. Barrier dysfunction due to impaired terminal differentiation of keratinocytes allows penetration of cutaneous antigens that initiates AD [10,11]. AD is a classical Th2-type disease with high levels of IL-4 and IL-13, although increased Th17 and Th22 cells can 1Immunology Service, Hospital de la also be detected [1]. Blockade of IL-4 receptor α chain clearly improves the outcome of AD Princesa, Instituto Investigación patients [12]. Sanitaria Princesa, Universidad Autónoma de Madrid, Madrid, Spain 2Centro de Investigación en Red de Both psoriasis and chronic AD lesions display cytokine-induced keratinocyte overgrowth, and Enfermedades Cardiovasculares, can be considered as proliferative disorders. Hence, epidermal cells may upregulate the expres- Madrid, Spain sion of nutrient transporters, like inflammatory cells, to perpetuate skin inflammation. However, whether keratinocytes and immune cells undergo similar or specific metabolic rewiring in psoria- *Correspondence: sis and AD diseases has not been examined in depth. The next sections are devoted to the role of [email protected] specific transporters and nutrient sensing pathways in these contexts. (F. Sánchez-Madrid).

Trends in Molecular Medicine, November 2020, Vol. 26, No. 11 https://doi.org/10.1016/j.molmed.2020.04.004 975 © 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Trends in Molecular Medicine

GLUTs and Metabolism in Skin Homeostasis and Inflammation Glossary Glucose is the major energy source for mammalian cells, fueling glycolysis and the tricarboxylic Aryl hydrocarbon receptor: aligand- acid (TCA) cycle (see Glossary)(Figure 1). There are two main families of GLUTs, GLUT and activated transcription factor that sodium-dependent glucose cotransporters (SGLTs) (Table 1). GLUT1 (SLC2A1) was the first regulates enzymes involved in the metabolism of xenobiotics as glucose transporter cloned, and is the most highly expressed in keratinocytes and activated cytochrome P450. This factor also binds endogenous molecules derived from tryptophan metabolism. Hypoxia-inducible factors: afamilyof transcription factors consisting of three alpha subunits, HIF-1α,HIF-2α,and HIF-3α. The HIF-1α and HIF-2α isoforms bind to hypoxia response element sequences and activate a transcriptional program dedicated to the adaptation of cells to reduced oxygen availability. It is currently unclear what role HIF-3α plays in modulating cellular response to hypoxia. Indoleamine 2,3-dioxygenase: enzyme for the first step of tryptophan catabolism through the kynurenine pathway. MYC: MYC proto-oncogene, bHLH transcription factor, encodes a nuclear phosphoprotein that participates in cell cycle progression, apoptosis and cellular transformation. Mechanistic target of rapamycin: serine/threonine kinase that function as master regulator of cell growth that senses and integrates nutritional and environmental signals. Oxidative phosphorylation: the final stage of cellular respiration that couples the electron transport chain with the ATP synthesis. The electron transport chain is composed of four complexes located in the inner membrane of mitochondria. Psoriasis Area and Severity Index: is a score used by clinicians to evaluate the severity of psoriasis that considers the

TrendsTrends inin MolecularMolecular MedicineMedicine intensity of redness, thickness and scaling of the skin lesions, and the Figure 1. Glucose and Amino Acid Catabolism and Its Interaction with the mTOR Pathway. Glucose taken up percentage of body area affected. through GLUT1 can be metabolized to pyruvate anaerobically by the glycolytic pathway, increasing the production of Tricarboxylic acid cycle or the lactate (green dots). Aerobic metabolism of glucose takes place in the mitochondria by the TCA cycle and OXPHOS Krebs cycle: sequential reactions that α pathway. Amino acids can also fuel the TCA cycle after being converted to acetyl-CoA or -keto acid intermediates like take place in the mitochondria and allow pyruvate, oxaloacetate, and succinyl-CoA. Functional coupling of Na/K pump, Na-dependent L-Gln transporters ASCT2, complete oxidation of glucose and the CD98–LAT1 heterodimer is required for L-Leu uptake. CD69 associates with the CD98–LAT1 heteromeric amino derivatives to CO2. acid transporter in activated lymphocytes. The mTOR pathway involves two distinct protein complexes, mTORC1 and mTORC2, that regulate cell proliferation and cell survival, respectively. Several GF-Rs and Cytok-Rs induce PI3K-mediated activation of AKT. Inhibition of TSC1/2 by PI3K/AKT phosphorylation, activates Rheb proteins. Amino acid stimulation activates Rag proteins allowing them to bind RAPTOR and recruit mTORC1 to the lysosomal surface, where Rheb is also located. Thus, mTORC1 signaling is only active when both Rag and Rheb are activated in response to GF in the presence of amino acids. Low energy conditions induce AMPK that activates mTORC2 complex while inhibits mTORC1 activity by induction of the inhibitory complex TSC1/2, and through the inhibitory phosphorylation of RAPTOR. Red color show amino acids regulation of mTOR pathway and energy production.Abbreviations:AKT,proteinkinaseB;AMPK,AMP- activated protein kinase; CAT1, cationic amino acid transporter 1; CoA, coenzyme A; Cytok-R, cytokine receptor; GF-R, growth factor receptor; GLUT1, glucose transporter 1; GSH, glutathione; LAT1, L-type amino acid transporter 1; mTOR, mechanistic target of rapamycin; mTORC, mTOR complex; OXPHOS, oxidative phosphorylation; PI3K, phosphatidylinositol 3-kinase; RAPTOR, regulatory-associated protein of mTOR; RICTOR, rapamycin-insensitive companion of mTOR; ROS, reactive oxygen species; TCA, tricarboxylic acid; TSC, tuberous sclerosis complex.

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Table 1. Glucose and Amino Acids Solute Carriers and Their Expression in Lesional Skin of Psoriasis and ADa Family Protein Gene Substrate Activity PSOR (assoc act) AD (assoc act) UniProtKB SGLT family of GLUTs SGLT SGLT1 SLC5A1 Glucose, galactose Symporter + + P13866 SGLT2 SLC5A2 Glucose Symporter + + P31639 SGLT5 SLC5A10 Mannose, fructose and glucose Symporter + + A0PJK1 SLC2A family of GLUTs SLC2A GLUT1 SLC2A1 Glucose Passive + (pos corr) [14,20] + P11166 GLUT2 SLC2A2 Glucose and fructose Passive + + P11168 GLUT3 SLC2A3 Glucose Passive + + P11169 GLUT4 SLC2A4 Glucose Passive + + P14672 GLUT5 SLC2A5 Fructose Passive + + (pos corr) P22732 GLUT7 SLC2A7 Glucose Passive ND ND Q6PXP3 GLUT8 SLC2A8 Glucose and fructose Passive + + Q9NY64 GLUT10 SLC2A10 Glucose Passive + + O95528 GLUT11 SLC2A11 Glucose Passive + + Q9BYW1 GLUT12 SLC2A12 Glucose Passive + + Q8TD20 GLUT14 SLC2A14 Glucose Passive + (neg corr) + (neg corr) Q8TDB8 System Protein Gene Substrate Activity PSOR (assoc act) AD (assoc act) UniProtKB Sodium-dependent neutral amino acid transporters A SNAT-1 SLC38A1 Ala, Gln, Ser Symporter + + Q9H2H9 SNAT-2 SLC38A2 Ala, Gln, Ser Symporter + + Q96QD8 SNAT-4 SLC38A4 Ala, His, Cys Symporter + + Q969I6 ASC ASCT1 SLC1A4 Ala, Ser, Cys, Thr Symporter + + P43007 ASCT2 SLC1A5 Gln, Asp, Ala, Ser, Cys, Thr Symporter + + Q15758 BETA GAT-1 SLC6A1 GABA Symporter + (pos corr) + P30531 GAT-2 SLC6A13 GABA, Tau Symporter + + Q9NSD5 GAT-3 SLC6A11 GABA Symporter + + P48066 BGT1 SLC6A12 GABA Symporter + + (pos corr) P48065 TAUT SLC6A6 Tau Symporter + + P31641 Gly GLYT1 SLC6A9 Gly Symporter + + P48067 GLYT2 SLC6A5 Gly Symporter ND ND Q9Y345 N SNAT3 SLC38A3 Gln, His, Ala, Asn, Glu Symporter ND ND Q99624 SNAT5 SLC38A5 Gln, Asn, Ser, His, Ala, Gly Symporter + ND Q8WUX1 PROT PROT SLC6A7 Pro Symporter ND ND Q99884 Sodium-independent neutral amino acid transporters ASCa ASC SLC7A10 Ser aUniporter + + Q9NS82 IMINO PAT1/LYAAT1 SLC36A1 Ala, Gly, Pro Symporter + + Q7Z2H8 PAT2/LYAAT2 SLC36A2 Ala, Gly, Pro Symporter + + Q495M3 La LAT1 SLC7A5 Leu, Phe, Trp, His, Met, Tyr aAntiporter + (pos corr) [36,39] + Q01650 LAT2 SLC7A8 Leu, Cys, Ala, Phe, Trp, Tyr, Ser, Arg, Thr aAntiporter + + Q9UHI5 LAT3 SLC43A1 Leu, Ile, Phe, Met, Val Uniporter + + (pos corr) O75387 LAT4 SLC43A2 Leu, Ile, Phe, Met, Val Uniporter + + (pos corr) Q8N370 T TAT1 SLC16A10 Trp, Phe, Tyr Uniporter + (pos corr) + Q8TF71

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Table 1. (continued) System Protein Gene Substrate Activity PSOR (assoc act) AD (assoc act) UniProtKB Sodium-dependent anionic amino acid transporters X-AG EAAT1 SLC1A3 Glu, Asp Symporter + (pos corr) + P43003 EAAT2 SLC1A2 Glu, Asp Symporter + + P43004 EAAT3 SLC1A1 Glu, Asp Symporter + + P43005 EAAT4 SLC1A6 Glu, Asp Symporter + + (neg corr) P48664 EAAT5 SLC1A7 Glu Symporter + + O00341 Sodium-independent anionic amino acid transporters Xc-a xCT SLC7A11 Cys, Glu aAntiporter + + Q9UPY5 Sodium-dependent cationic amino acid transporters B0+ ATB(0+) SLC6A14 Ile, Leu, Met, Phe, Trp, Val, Ser Symporter + + Q9UN76 y+La y+LAT1 SLC7A7 Arg, Leu, Gln aAntiporter + (pos corr) + Q9UM01 y+LAT2 SLC7A6 Arg, Leu, Gln aAntiporter + (neg corr) + Q92536 Sodium-independent cationic amino acid transporters B0+ B(0,+)AT1 SLC7A9 Cys Uniporter + + P82251 y+ CAT-1 SLC7A1 Arg, Lys Uniporter + + P30825 CAT-2 SLC7A2 Arg, Lys Uniporter + + P52569 CAT-3 SLC7A3 Arg, Lys Uniporter ND ND Q8WY07 CAT-4 SLC7A4 Arg, Lys Uniporter + + O43246 a+ Expression detected by RNAseq, from of GEO datasets (GSE67785, GSE121212) PMID: 26251673, 30641038. Association with disease activity (assoc act) is indi- cated as a positive or a negative correlation (pos corr, neg corr). aAssociation with CD98 is required. Abbreviations: ND, not described in GSE67785 or GSE121212; PSOR, psoriasis patients.

T lymphocytes [13–15]. Although there are no previous reports indicating the relevance of glycolysis versus oxidative phosphorylation (OXPHOS) in human skin homeostasis and inﬂamma- tion, some clues arise from experiments in which glycolysis or GLUT1 expression has been targeted in T cells and keratinocytes.

Increased expression of GLUT1 and engagement of the glycolysis pathway underlie secretion of IL-17 and IL-4 (Box 1)[15]. Metabolomic studies using serum samples from AD patients revealed lower levels of β-oxidation metabolites and increased anaerobic glycolysis-derived lactate [16]. In contrast, activation of lipid metabolic pathways is also a prominent feature of Th2 cells [17], suggesting its possible role in AD.

Genetic deletion or inhibition of GLUT1 reduces glucose transport by 95% in keratinocytes, underscoring the role of GLUT1 as the main GLUT in the epidermis [14]. GLUT1 plays a role in keratinocyte proliferation [14] and its expression is upregulated in UV-irradiated mouse skin [18], during wound healing responses [19], and in psoriasis [20,21]. Nevertheless, no apparent abnormalities are observed in the skin of mice with targeted deletion of GLUT1 in keratinocytes, suggesting that amino acids, fatty acids, or other hexoses are mainly used as alternative sub- strates for the TCA cycle (Figure 1)[14].

The levels of GLUT1 expression positively correlates with the Psoriasis Area and Severity Index (PASI) score. They also correlate with increased epidermal thickness, inﬂammatory cell density, microvessel density [20], and Ki-67 expression [21]. Genetic or pharmacological

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Box 1. Metabolic Requirement of T Cell Activation and Differentiation Naïve T cells are quiescent, and their energy metabolism is largely dependent on the TCA cycle and OXPHOS pathway. Antigen recognition by the TCR increases GLUT1 expression and induces metabolic reprogramming towards aerobic glycolysis, in which glucose is mainly converted into lactate (see Figure 1 in main text) [90,91]. Activated CD4+ T cells can differentiate into distinct helper cell lineages that have different metabolic needs. Th1, Th2, and Th17 cell subsets display elevated GLUT1 and glycolytic rates, Treg cells maintain the OXPHOS pathway [92]. In addition to the generation of effector T cells, a small fraction of activated T cells differentiates into precursor memory T cells, that lead to TCM cells, effector memory T cells, and TRM cells. Most skin T cells are TRM and Treg cells. TRM cells are crucial in the recurrence of chronic inﬂammatory skin diseases, like psoriasis or AD [93,94]. Similar to Treg cells, the preferential energy source of skin TRM cells is oxidation of fatty acid and OXPHOS [95], underscoring their ability to adapt to the local skin microenvironment. In addition to glycolysis, effector T cells also use glutaminolysis as their main energy source [90,91]. For this purpose, the expression of Gln transporters, mainly SNAT1 (SLC38A1) and ASCT2 (SLC1A5), are upregulated by MYC after TCR and CD28 costimulation [26].

mTOR involves two distinct protein complexes, mTORC1) and mTORC2 (see Figure 1 in main text). RAPTOR and the rapamycin-insensitive companion of mTOR (RICTOR) are both mTOR-associated adaptor proteins required for the formation and function of mTORC1 and mTORC2, respectively. mTORC1 activation promotes protein synthesis and proliferation through the phosphorylation of p70S6 kinase 1 and eIF4E binding protein (4EBP), which regulate mRNA translation initiation. mTORC2 controls cell survival and migration by phosphorylating protein kinase C, serum- and glucocorticoid-induced protein kinase 1 (SGK1), and AKT.

TCR and CD28-induced signaling leads to activation of the PI3K/AKT/mTOR pathway [91]. Importantly, mTORC1 enhances HIF1α expression at both the transcriptional and translational level, and thereby further stimulates glycolysis and glucose transport [91]. Activation of mTOR is essential for Th1, Th2, and Th17 effector lineages [96]. On the contrary, mTOR deletion or inhibition induces differentiation into Foxp3+ Treg cells [96] (see Figure 2 in main text). targeting of GLUT1 in keratinocytes dampens imiquimod (IMQ)-induced psoriasiform hyperplasia [14]. While deletion of GLUT1 in keratinocytes mostly prevents epidermal acanthosis and proliferation, chemical inhibition of GLUT1 also decreases inflammatory infiltration [14], indicating that immune cells can be thus targeted. Further studies to specifically target GLUT1-mediated glucose uptake by immune cells are required to precisely dissect the usefulness of this approach. Importantly, hypoglycemic agents used for the treatment of type 2 diabetes seem to exert beneficial effects in psoriasis through different mechanisms, including a reduction of energy consumption [22].

Amino Acid Transporters and Metabolism in Skin Homeostasis and Inflammation There are 11 families of solute carrier genes involved in amino acid transport in humans: SLC1, SLC3, SLC6, SLC7, SLC16, SLC17, SLC25, SLC32, SLC36, SLC38, and SLC43 [23]. The SLC25 (mitochondrial transporters), and SLC17 and SLC32 (vesicular transporters) family members are beyond the scope of this review. CD98 protein (SLC3A2) forms disulfide-bound hetero- dimers with members of the SLC7 family that determine the substrate specificity of the complex [23](Table 1). Based on their substrate specificity, transport mechanism and regulatory properties, amino acid transporters expressed in the plasma membrane can be classified as sodium- dependent and -independent neutral, anionic, and cationic amino acid transporters (Table 1). Although evidence is still scant, in vitro and in vivo data suggest their relevance in the development and recurrence of skin inflammation. Public data from RNAseq analysis (GSE67785 and GSE121212) of skin biopsies revealed the expression of several nutrient carriers in psoriasis and AD lesions, and some of them correlate with disease severity indices (Table 1)[24,25].

In activated T cells, L-Gln transport can be mediated by ASCT2 (SLC1A5) and SNAT1 (SLC38A1) [26]. L-Gln removal from the medium blocks T cell proliferation and interferon (IFN)γ secretion [27]. Also, ASCT2-deﬁcient CD4 T cells fail to differentiate towards Th1 and Th17 lineages, but can be- come Th2 or T regulatory (Treg) cells [28]. Thus, inhibition of L-Gln uptake might be effective to control psoriasis but not AD ]. Accordingly, L-Gln has anti-inﬂammatory properties in a model of

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dermatitis induced by 1-fluoro-2,4-dinitrobenzene [29]. Moreover, Gln-enriched enteral nutrition of very low-birth-weight infants decreased the incidence of AD [30]. The specificaminoacid transporter required for L-Gln uptake by keratinocytes, or its potential regulation during inflammation have not been described in psoriasis or AD. Nevertheless, genetic variants of both Gln transporters ASCT2 and SNAT1 have been associated with psoriasis risk in a genome-wide pathway analysis study [31].

Comparative analysis of plasma metabolomic profiles showed that levels of several amino acids including L-Leu, L-Phe, and L-Trp, were significantly higher in the plasma of psoriasis patients compared with those detected in healthy volunteers [32]. These amino acids are mainly transported by members of the LAT family, including LAT1 (SLC7A5) (Table 1). LAT1 is the main L-Leu transporter, and it is over-represented in activated T cells [26], B cells [33], macrophages [34] natural killer cells [35], and IL-17-secreting γδ T cells [36]. LAT1 deficiency prevents metabolic reprogramming and mechanistic target of rapamycin (mTOR) activation after T cell receptor (TCR) activation [26], reducing ability to differentiate towards Th1, Th17, and Th2 but not to Treg cell lineages [26,36,37]. Structurally, LAT1 forms a heterodimer with CD98, which stabilizes its expression and enables its function on the plasma membrane [38]. However, this molecular complex can be further regulated in activated lymphocytes by expression of CD69 [39], also expressed in tissue resident memory (TRM) cells [40]. Expression of CD69 increases amino acid uptake through LAT1, including L-Trp, which is the source of different ligands for the activation of the transcriptional factor aryl hydrocarbon receptor (AHR). Among other targets, AHR controls IL-22 secretion induced by IL-23 [39]. Specific deletion or inhibition of LAT1 in IL17+ γδ T cells also controls IL-23 and IL-1β-induced proliferation and secretion of IL-17 and IL-22, conferring protection against IMQ-induced psoriasiform hyperplasia [36]. Moreover, a chemical inhibitor of LAT1 efficiently controls inflammation and TH2 differentiation in an ovalbumin-induced model of AD [37]. Increased expression of LAT1, LAT2, and LAT3 essential amino acid transporters has been reported in the epidermis of psoriasis patients [36]. LAT2 associates with CD98, while LAT3 is a unidirectional and monomeric amino acid transporter regulated by the substrate gradi- ent (Figure 2). Genetic deletion of LAT1 in keratinocytes was not sufficient to control epidermal proliferation in the IMQ model, indicating a possible compensatory function of LAT2 and LAT3 transporters [36].

Besides LAT1 and LAT2, CD98 also binds to xCT, y+LAT1, y+LAT2, or ASC1 (Table 1)[41]. The CD98-xCT complex sustains cellular redox homeostasis by taking up cysteine, which is neces- sary for glutathione biosynthesis (Figure 1)[42]. xCT (SLC7A11) gene alterations are associated with increased psoriasis risk, along with y+LAT1 (SLC7A7), LAT4 (SLC43A2), CAT1 (SLC7A1), ASCT1 (SLC1A4), SNAT1 (SLC38A1), and especially TAT1 (SLC16A10) [31]. CD98 deletion also affects GLUT1 expression in the membrane [43] and nucleotide levels, preventing cell cycle progression [41]. Although CD98 and LAT1 are required for Th1 differentiation, [26,44], deletion of CD98 but not LAT1 affects Treg cell differentiation [26,45]. Moreover, CD98 deletion in the epidermis affects skin homeostasis and wound healing response [46], thus hindering its potential as a target to control skin inﬂammation.

In addition to its role as a protein building block, L-Arg is also the precursor of multiple metabolites, including NO. The expression of L-Arg transporter CAT1 is increased upon T cell activation [47]. Activation of T cells in the absence of L-Arg triggers the general control non-derepressible 2 (GCN2) kinase signaling pathway, inducing cycle arrest [48]. Importantly, increased intracellular L-Arg levels skew the metabolism of activated T cells from glycolysis towards mitochondrial OXPHOS, limiting Th1 differentiation and promoting the generation of central memory T (TCM) cells [47]. L-Arg metabolism also plays an important role in macrophage polarization [49].

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Inducible NO synthase (iNOS)-derived NO produced by keratinocytes is an important regulator of gene expression, wound healing, and proliferation [50]. Keratinocytes constitutively express CAT1 and CAT2, and microenvironmental L-Arg uptake is essential for the activities of iNOS and arginase, which in turn modulate proliferation and differentiation of human epidermal skin cells [51]. Moreover, proinﬂammatory cytokines such as TNF and IL-1β upregulate CAT2 and iNOS expression in keratinocytes [51]. Competitive inhibition of L-Arg transport by L-Lys signiﬁ- cantly decreases keratinocyte proliferation [51], underscoring the relevance of the composition of the extracellular medium as a biological modulator. Arginase is overactive in psoriatic skin, leading to a relative increase in the consumption of L-Arg [52,53]. L-Arg plasma concentration is low in psoriasis patients, whereas L-ornithine (an arginase product) is increased [54]. Although the regulation of CAT1 and CAT2 has not been comparatively analyzed in AD patients, arginase levels are low in these patients [55,56], correlating well with higher L-Arg plasma levels [56], thus indicating the possible existence of a differential mechanism of L-Arg metabolism between both diseases.

Although L-Gln is the preferred substrate of SNAT1 and ASCT2, they can also mediate the uptake of L-Ala and L-Ser (Table 1). Extracellular L-Ala uptake through SNAT1 is required for efficient activation of naïve T cells, memory T cell re-stimulation, and IFNγ and TNFα secretion [57]. L-Ser uptake is also important for de novo nucleotide biosynthesis in proliferating T cells, as its depletion decreased T cell proliferation without affecting the expression of activation markers (CD69, CD25, and CD44) and IFNγ [58]. Increased levels of circulating amino acids, including L-Arg, L-Ala, and L-Glu could be useful to monitor the severity of the disease and gauge the therapeutic response to anti-TNFα antibodies [32,59]. Importantly, treatment with an antibody against TNFα shifts the majority of psoriasis-associated trends in circulating metabolites towards that of healthy controls, underscoring that the severity of psoriasis is clearly linked to high levels of circulating amino acids [32]. However, the role of L-Ala and L-Ser transporters as potential targets to control psoriasis and AD diseases has yet to be analyzed. Furthermore, activation of the GCN2 pathway in response to amino acid starvation is required for normal epidermal differentiation of keratinocytes (Figure 2)[60]. In T cells, GCN2 kinase activation mediates proliferative arrest and anergy induction by indoleamine 2,3-dioxygenase, which catabolizes L-Trp [61]. In summary, homeostasis demands reduced levels of amino acids in the skin to curb skin lymphocyte proliferation and trigger proper keratinocyte differentiation. Although it is not clear whether alteration of amino acid levels can indeed trigger skin inflammation, they are important targets that can be modulated at different levels, including dietary uptake, reduction of specific transporters or metabolic usage (see Clinician’s Corner).

Figure 2. Increased Metabolic Demands of Lymphocytes and Keratinocytes in Skin Inflammation. (A) In homeostasis, skin TRM and Treg cells obtain ATP from glucose and fatty acids oxidation by the OXPHOS system. Reduced amino acids uptake activates GCN2 and curbs the mTOR pathway, decreasing proliferation. TGFβ- induced signaling upregulates FOXP3 and IL-10 secretion in Treg cells. During inflammation, antigen recognition and pro-inflammatory cytokines like IL-23 and IL-1β induce mTOR pathway, increasing proliferation and secretion of Th1 and Th17 lineages-related cytokines. mTORC1 increases the activity of HIF1α,thatalongwith TCR-induced MYC transcriptional factor upregulate glucose and amino acid metabolism. (B) Similar to T cells, keratinocytes during homeostasis display reduced glucose and amino acid uptake, which supply carbon atoms to the TCA cycle and OXPHOS system. Under conditions of essential amino acid limitation, GCN2 kinase phosphorylates eIF2α, inhibiting global mRNA translation but upregulating transcription factor ATF4, which increases the expression of many stress response genes including CHOP, that regulate ROS defense systems. Amino acid deprivation reduces mTOR signaling and increased autophagy flux. These pathways simultaneously control differentiation and reduce the proliferation of epidermal cells. In psoriatic lesions, keratinocytes show increased levels of GLUT1 and LAT amino acid transporters, activation of mTOR, HIF1α, and glycolysis. Arg-uptake through CAT amino acid transporter differentially controls NO synthesis in psoriasis and atopic dermatitis (AD) patients. Increased MYC and HIF1α expression are detected in keratinocytes of psoriasis and AD patients, suggesting their role in the inflammation- induced metabolic alterations of the skin. Abbreviations: AA, amino acid; AKT, protein kinase B; CAT, cationic amino acid transporter; Cytok-R, cytokine receptor; EGF-R, epidermal growth factor receptor; eIF2α, eukaryotic initiation factor 2α; FOXP3, forkhead box P3; GCN2, general control non-derepressible 2; GLUT1, glucose transporter 1; HIF1α, hypoxia-inducible factor 1α; IL, interleukin; LAT, L-type amino acid transporter; mTOR, mechanistic target of rapamycin; mTORC1, mTOR complex 1; OXPHOS, oxidative phosphorylation; PI3K, phosphatidylinositol 3-kinase; RORγt, RAR-related orphan receptor γt; ROS, reactive oxygen species; TCA, tricarboxylic acid; TCR, T cell receptor; TGFβ-R, transforming growth factor β receptor; Th1/17, T helper 1/17; Treg cell, T regulatory cell; TRM cell, tissue-resident memory cell.

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Clinician’s Corner MYC and HIF Metabolic Checkpoints as Potential Targets to Treat Skin Amino acids can compensate for the Inflammation deficiency in carbon supply induced TCR and CD28 stimulation induces MYC transcription factor that upregulates GLUT1 expression by GLUT1 inhibition. For this reason, combined topical administration of and other enzymes of the glycolytic pathway [62]. MYC also upregulates the levels of enzymes GLUT1 and LAT1 inhibitors, could be required for glutaminolysis and amino acid transporters such as LAT1, SNAT2, and ASCT2 a novel strategy to control psoriasis [62,63]. LAT1 deletion prevents MYC transcriptional activity, inducing alterations in the glucose and AD. and L-Gln metabolism [26,35,64]. MYC also transcriptionally regulates LAT3 expression in cancer Nutritional interventions controlling cells [64], an amino acid transporter highly expressed in psoriasis [36]. glucose and specificaminoacids uptake could be effective to prevent TCR signaling also induces oxygen-independent stabilization of hypoxia-inducible factor (HIF)- the progression of skin inflammation. α α 1 and HIF-2 transcriptional factors, through a mechanism that involves mTOR activation mTOR inhibition as an [65,66]. HIF-1α is a key mediator in the switch from oxidative to glycolytic metabolism, increasing immunosuppressive strategy may the expression of GLUT1 and glycolytic enzymes, while repressing OXPHOS [66]. Furthermore, induce off target adverse secondary fi HIF-1α enhances Th17/Treg cell ratio through direct transcriptional activation of RAR-related effects. However, inhibition of speci c γ nutrient transporters such as LAT1 orphan receptor (ROR) t and targeting forkhead box (Fox)p3 for proteasomal degradation [67]. and GLUT1 could target highly The role of HIF-2α in T cell activation and immune response is less known than that of HIF-1α. metabolic demanding proliferating HIF-2α transcriptionally controls LAT1 in tumor cells, potentiating mTOR activation and prolifera- cells such as keratinocytes and active tion [68]. However, whether HIF-2α regulates LAT1 expression in activated immune cells has not lymphocytes. been explored so far.

MYC is increased in a significant percentage of epithelial cells from psoriatic skin lesions compared to uninvolved or healthy skin [69,70]. HIF-1α and its main target vascular endo- thelial growth factor (VEGF)-A are highly expressed in psoriatic skin [71], suggesting a role for HIF-1α in angiogenesis in this context. Also, HIF-1α overexpression in keratinocytes promotes proliferation and inhibits terminal differentiation [72], while HIF-2α deletion promotes wound closure [73]. HIF-1α and HIF-2α regulate filaggrin expression and barrier function [74]. Moreover, HIF-2α regulates IL-31 induction; a major pruritogen associated with AD [75]. Although these preliminary data point out a role for both HIF isoforms and MYC in the control of inflammatory cells and keratinocyte metabolic rewiring in skin chronic inflammation, further studies are required to evaluate their potential as novel therapeutic targets (Figure 2). mTOR Pathway in Skin Homeostasis and Inflammation mTOR is a Ser/Thr kinase that senses environmental nutrients and growth-factor-derived signals to coordinate cell growth, survival, and proliferation [76]. mTOR activation controls the protein, nucleotide, and lipid biosynthesis machinery required for cell proliferation and cytokine release, and is regulated by energy and amino acids levels, mainly L-Leu, L-Gln, and L-Arg (Figure 1 and Box 1)[77].

The mTOR pathway is activated in γδ T cells in response to innate stimuli such as IL-1β and IL-23 [36](Figure 2). mTOR inhibition blocks the proliferation of IL-17 secreting γδ T cells induced by combination of IL-23 and IL-1β [36]. In addition, mice bearing speciﬁc deletion of mTOR complex (mTORC)1 or mTORC2 reveal that they are essential for γδ T cell proliferation [78]. Increased mTORC1 signaling is found in peripheral blood mononuclear cells of psoriasis patients [79]. Moreover, Treg cells from psoriasis patients also show increased mTOR, and methotrexate controls its activation [80]. The mTOR pathway can also contribute to pathogenesis of psoriasis by controlling secretion of proinﬂammatory mediators by keratinocytes, including IL-6, chemokine CXC ligand 8, or VEGF, induced by TNFα [81].

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mTOR signaling also plays a fundamental role in epidermal morphogenesis and the formation of Outstanding Questions the epidermal barrier [82]. Upregulation of mTOR signaling proteins in psoriatic skin [83,84] indi- Does the increment of GLUT1 in kerati cates its role in enhanced proliferation and defective keratinocyte differentiation. In addition, nocytes point out to glycolysis as the mTOR is upregulated by IL-22, IL-17, and IFNγ signaling in keratinocytes [85,86]. Topical appli- main source of energy compared with OXPHOS during psoriasis and AD? cation of rapamycin ameliorated erythema, scaling, and skin thickness in the IMQ-induced psoriasiform hyperplasia [84]. Moreover, systemic administration of rapamycin prevents expan- Is the inhibition of glycolysis or OXPHOS sion of IL17-secreting γδ T cells, as well as dampens IL-17 and IL-22 secretion by γδ and CD4 in the epidermis a potential mechanism to regulate keratinocyte proliferation, ter- T cells in the same model [36]. minal differentiation, cytokine release, and barrier function? The role of mTOR in AD is less characterized than in psoriasis. However, topical application of rapamycin in a mouse model of AD improves several parameters, including dermal inflamma- What is the role of glutamine transporter fi system and glutaminolysis in keratino tory in ltrate, serum IgE levels, and Th2 and Th1 cytokine levels [87,88]. Moreover, increased cytes in homeostasis, psoriasis, and AD? transcriptional levels of regulatory-associated protein of mTOR (RAPTOR) correlate with decreased filaggrin expression in patients with AD [89]. In fact, a genetic variant inducing in- Could the inhibitors of CATs be useful creased activation of mTORC1 impairs filaggrin processing, causing barrier defects and pro- therapeutic tools in psoriasis and AD? moting inflammation [89]. Could agonists of the GCN signaling pathway and autophagy be used to control psoriasis? Concluding Remarks Might modifications of dietary habits or Metabolic pathways can control the activation and differentiation of immune cells and the monitoring of circulating glucose keratinocytes, mainly through the mTOR pathway, in chronic skin inflammatory diseases and amino acid levels be preventive such as psoriasis and AD. However, our knowledge of the role of several amino acid trans- strategies to the onset of psoriasis porters including CAT1, CAT2, ASTC2, SNAT1, and xCT in psoriasis and AD is scarce. Fur- and AD? ther studies are required to elucidate their relevance for the treatment of skin diseases. Although increased expression of metabolic checkpoints like MYC and HIF have been observed in the lesions of psoriatic patients, they have not been directly evaluated as therapeutic targets for the control of psoriasis or AD (see Outstanding Questions). Moreover, comparative metabolomic studies of psoriasis and AD patients are required to ascertain whether alterations of specific metabolites, locally or systemically, can trigger signaling pathways that regulate disease progression. These could be translated to nutritional strategies targeting glucose and specific amino acid uptake in order to control psoriasis or AD progression (see Clinician’sCorner).

Acknowledgments Authors thank Dr. Miguel Vicente-Manzanares for critical review and editing. This review was funded by grant SAF2017- 82886-R from the Spanish Ministry of Economy and Competitiveness (MINECO), grant S2017/BMD-3671-INFLAMUNE- CM from the Comunidad de Madrid, a grant from the Ramón Areces Foundation 'Ciencias de la Vida y la Salud' (XIX Concurso-2018) and a grant from Ayudas Fundación BBVA a Equipos de Investigación Cientíﬁca (BIOMEDICINA-2018), and 'La Caixa' Banking Foundation (HR17-00016).

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