Amino Acid Solute Carrier Transporters in Inflammation and Autoimmunity

GS, glutamine endogenous retrovirus; intestinal enteroids; immunodeficiency HOXB9, homeobox cells; sarcoma-associated herpesvirus; lysinuric protein intolerance; myeloid-derived SLCs, T-ALL, T-cell lymphoblastic ulcerative colitis; VSV, stomatitis West Abstract The past decade exposed the importance of many homeostasis and metabolism related proteins in autoimmunity disease and inflammation. Solute carriers (SLCs) are a group of membrane channels that can transport amino acids, the building blocks of proteins, nutrients, and neurotransmitters. This review summarizes the role of SLCs amino acid transporters in inflammation and autoimmunity disease. In detail, the importance of Glutamate transporters SLC1A1, SLC1A2, and SLC1A3, mainly expressed in the brain where they help prevent glutamate excitotoxicity, is discussed in the context of central nervous system (CNS) disorders such as multiple sclerosis. Similarly, the cationic amino acid transporter SLC7A1 (CAT1), which is an important arginine transporter for T cells, and SLC7A2 (CAT2), essential for innate immunity. SLC3 family proteins, which bind with light chains from the SLC7 family (SLC7A5, SLC7A7 and SLC7A11) to form heteromeric amino acid transporters, are also explored to describe their roles in T cells, NK cells, macrophages and tumor immunotherapies. Altogether, the link between SLC amino acid transporters with inflammation and autoimmunity may contribute to a better understanding of underlying mechanism of disease and provide novel potential therapeutic avenues. and SLC7 link may understanding and provide potential therapeutic targets and researchers who amino acids in immunity.

In fact, one in every five Americans suffers from at least one chronic inflammatory condition, and 3-5% of an autoimmunity disorder (Wang et al,2015). Traditionally, inflammatory and metabolic diseases were often approach separately, but the past decades have highlighted the importance of metabolic dysbiosis in chronic inflammation and autoimmunity disorders (Compston and Coles,2008, Sospedra and Martin,2005, Pitt et al,2000. For example, multiple sclerosis (MS) is exacerbated by excessive glutamate transport and excitotoxicity, mediated by SLC proteins. Similarly, L-arginine transport, also mediated by SLCs, regulates multiple innate inflammatory mechanisms such of arginase-1 (ARG1) activity and inducible nitric oxide synthase (iNOS, NOS2).
The SLC superfamily is a large group of membrane transporters with over 65 families and more than 400 members. SLCs play important roles in nutrient and metabolic sensing (Zhang et al,2019, Chen et al,2019, and metabolic regulation of immune cells (Song et al,2020). Structurally SLCs can be tremendously diverse with a myriad of substrates; and while several SLCs act as drug transporters (Liang et al,2015), many others can transport amino acid across membranes, such as members of SLC1 and SLC7 families (Table 1).
The SLC1 family of transporters, named high-affinity glutamate and neutral amino acid transporter family, comprises five excitatory amino acid transporters (EAATs) of the X -AG system, and two alanine serine cysteine transporters (ASCTs) of the ASC system. The ASC system includes the two neutral amino acid transporters of the SLC1 family, SLC1A4 (ASC transporter 1) and SLC1A5 (ASC transporter 2) (Kanai et al,2013). The X -AG system includes SLC1A1 (EAAC1), SLC1A2 (GLT1, EAAT2), SLC1A3 (GLAST, EAAT1), SLC1A6 (EAAT4) and SLC1A7 (EAAT5), which are high-affinity glutamate transporters responsible for L-glutamate and D/L-aspartate uptake with cotransport of three sodium ions (Na + ) and one proton (H + ), and counter-transport of one potassium ion (K + ) (Kanai et al,2013). In the brain, SLC1A1 is mainly expressed in neurons; SLC1A2 in astrocytes, Bergmann glia and neurons; and This article has not been copyedited and formatted. The final version may differ from this version. SLC1A3 in astrocytes and Bergmann glia (Kanai et al,2013), all with important functions in the CNS ( Figure 1).
The SLC7 family of transporters, named cationic amino acid transporter/glycoprotein-associated family, are divided into two subfamilies: the cationic amino acid transporters (CATs), and the L-type amino acid transporters (LATs). CATs include SLC7A1-4 and SLC7A14, which mediate Na + independent transport of cationic L-amino acids (Fotiadis et al,2013); while LATs are the light or catalytic subunits of heteromeric amino acid transporters (HATs) with a broad spectrum of substrates (Fotiadis et al,2013), which are linked to the heavy subunits 4F2hc(SLC3A2) or rBAT(SLC3A1) through disulfide bonds.
SLC7 transporters are important metabolic regulators in immune cells as summarized in Figure 2.
In this review, the role of SLCs amino acids transporters in inflammation and autoimmunity and its supporting literature discussed in detail. First, the part of SLC7 family members in innate and adaptive immune cells is debated, followed by the importance of SLC1 family proteins in neural inflammation, particularly in MS. Similarly, the role of SLCs in viral and bacterial infections is also analyzed, along with a brief summary on the impact of SLCs in other inflammatory disorders. Finally, the prospect of SLC based therapeutics is explored.

SLCs function in innate and adaptive immune cells
The immune system is a complex biological network, traditionally separated in innate and adaptive immune cells. Innate immune cells such as Macrophages, Dendritic cells and NK cells are generally the first responders, driving inflammation through antigen-independent mechanisms. Adaptive immune cell, such as T and B-cells, are activated by innate immune signals and drive antigen-specific memory immunity.
SLC7A2 is highly involved in both innate and adaptive immunity. Slc7a2 expression was induced in both classical (M1) and alternative (M2) activated in macrophages, and Slc7a2 knockout blocked arginine transport and limited its activity after macrophage activation (Yeramian et al,2006). Furthermore, This article has not been copyedited and formatted. The final version may differ from this version. Platonin, an inhibitor of acute inflammation, lowered NO production and arginine transport in LPSstimulated mouse macrophages via iNOS and SLC7A2 inhibition (Chen et al,2006). Slc7a2 expression in peripheral monocytes was also found to be upregulated in pregnancy and was higher in preeclampsia, during which systemic inflammation is widespread and the arginine transport is strengthened (McCord et al,2006). The lung of SLC7A2 deficient mice show signs of spontaneous inflammation accompanied by increased DC and alveolar macrophages activation, but with compromised NO production (Rothenberg et al,2006). Finally, Myeloid-derived suppressor cells (MDSCs) suppressed T cell activities under inflammation or tumor conditions through increased arginine metabolism, while SLC7A2 deficiency promoted antitumor immunity (Bozkus et al,2015).
SLC7A7 also affects amino acid transport, differentiation and immune function of macrophages. Slc7a7 mRNA, SLC7A7 protein levels and arginine transport were increased during monocyte differentiation to macrophages mediated by PKC activation. Contrastingly, the y + system and y + L system mainly transported arginine and lysine outwards of macrophagic cells (Barilli et al,2011). Silencing of Slc7a7 in human THP-1 macrophages and A549 epithelial cells induced secretion of IL-1β, and TNF-α via the NF-κB pathway, and CCL5/RANTES stimulated by IL-1β signaling feedback, which were independent of arginine concentration. Thus, Slc7a7 likely plays a deeper role in inflammation aside of arginine transport (Rotoli et al,2018). Mutation of Slc7a7 could also cause lysinuric protein intolerance (LPI), in which arginine transport by system y + L was impaired in macrophages and phagocytic activity was severely damaged (Barilli et al,2012). In LPI patients, plasma pro-inflammatory chemokines were higher, and LPI macrophages exhibited impaired response to TLR9 stimulation, higher response to TLR2/1 and TLR4 stimulation, and lower NO production (Kurko et al,2015). SLC7A5 mediated leucine transport in macrophages promoted mTORC1 signaling and pro-inflammatory cytokine production (Yoon et al,2018). Slc7a5 expression was upregulated in monocytes from rheumatoid arthritis (RA) patients and healthy monocytes following LPS stimulation. Additionally, Slc7a5 expression levels positively correlated with RA clinical condition indicating a relationship of SLC7A5 with inflammation (Yoon et al,2018). Similarly, a natural alkaloid piperine promoted mTORC1 signaling via recruitment of membrane SLC7A5/CD98, synthesis of IL-6 and TNF-α, and phagocytic activity against bacteria in peritoneal macrophages (Pan et al,2015). In activated NK cells, SLC7A5 also acted as a predominant amino acid transporter and together with glutamine supply, was essential for maintaining c-Myc and NK cell function (Loftus et al,2018).
Still in macrophages, treatment with amphibole asbestos increased SLC7A11 expression, while SLC7A11 inhibition led to oxidative stress and cell death, which could be rescued by cystine (Pfau et al,2012).
SLC7A11 was identified as a macrophagic host factor in the vesicular stomatitis virus (VSV) replication (Kandasamy et al,2016), and in LPS-stimulated macrophages, SLC7A11 deficiency caused insufficient cysteine supply, decreased nitrite in the culture medium and an increase in reactive oxygen species (ROS) (Kobayashi et al,2018). LPS stimulation in hippocampus elevated SLC7A11 expression, and knockout of SLC7A11 relieves peripheral and central inflammation and the effect of LPS stimulation in mice (Albertini et al,2018). SLC7A11 was also elevated in IL-4-induced M2 macrophages during parainflammation and is related to M2 genes (Wang et al,2020a). SLC7A11 (xCT) forms system x c with CD98 and is mainly expressed in the brain, macrophages, and cell lines, and acts as a Na + -independent transporter of extracellular anionic cystine and intracellular glutamate (Fotiadis et al,2013). For T cells, although in vitro proliferation was SLC7A11-dependent, in vivo proliferation, immune response, and memory effects were SLC7A11-independent; therefore, using SLC7A11 as an antitumor therapeutic target should not affect T cell immune response (Arensman et al,2019). Although baseline SLC7A11 levels are relatively low in T cells, thermal injury strongly induces SLC7A11, resulting in cystine import and T cell dysfunction (D'Elia et al,2009). Glutathione (GSH) production in part mediated by SLC7A11 can limit ROS accumulation and support the activity of mTOR and nuclear factor of activated T cells (NFAT) to drive glycolysis and glutaminolysis in activated T cells (Mak et al,2017).
In NK cells, IL-2 priming could upregulate SLC1A5 and SLC3A2 (CD98), which were both necessary for IFN-γ production and degranulation by NK cells following stimulation of the activating receptor, natural-killer group 2 member D (NKG2D) (Jensen et al,2017). SLC1A5 participates in adaptive immunity as a conditionally essential glutamine transporter. SLC1A5-dependent rapid glutamine uptake occurred during naïve T cell activation, and SLC1A5 deficiency caused failure of Th1 and Th17 cell induction, as well as loss of the inflammatory T cell responses (Nakaya et al,2014). Glutamine uptake through SLC1A5 and T cell receptor (TCR) signaling complex were both necessary for mTORC activation by TCR stimulation (Nakaya et al,2014). Further, glucose and glutamine were both required upon B cell activation (Jiang et al,2018). Overexpression of the microRNA cluster let-7adf reduced levels of both glucose by targeting hexokinase two and glutamate by inhibition of SLC1A5 and glutaminase, and further controlled antibody production of B cells (Jiang et al,2018). However, SLC1A5 knockout in mice was reported to have no influence on B cell development, proliferation, or function (Masle-Farquhar et al,2017). Blocking SLC1A5 with GPNA to inhibit the uptake of glutamine can significantly enhance the inhibitory effect of cetuximab on the proliferation of gastric cancer and metastatic colorectal cancer (CRC) in vivo and in vitro. Research provides the metabolic role of SLC1A5 as potential therapeutic target to improve the efficacy of cetuximab for CRC and gastric cancer (Ma et al,2021, Ma et al,2018. SLC7A1 seems to be the major system y + transporter in most cell types (Fotiadis et al,2013). SLC7A1 expression was increased in CD8 + T cells and naïve and memory CD4 + T cells to provide sufficient arginine for T cell function (Werner et al,2016). In contrast, Slc7a1 expression was not induced by classical or alternative activation of macrophages (Yeramian et al,2006). Meanwhile, Slc7a5 -/-T cells showed impaired proliferation, differentiation or metabolically reprogramming upon antigen stimulation, and leucine transport by L system was required for mTORC1 activity and c-Myc expression in activated This article has not been copyedited and formatted. The final version may differ from this version. T cells (Sinclair et al,2013). The lack of methionine may also be responsible for the halt of protein production in Slc7a5 -/-T cells, similar to the effect of Myc deletion (Marchingo et al,2020). SLC7A5 inhibition as well as amino acid starvation triggered expression of homeobox B9 (HOXB9) in activated T cells, which attenuated production of selective cytokines (Hayashi et al,2016). SLC7A7 participated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) (Ji et al,2018).

SLCs in neural inflammation and autoimmunity (multiple sclerosis)
Neurological diseases afflict 3-5% of the global population. Multiple sclerosis alone affects 59/100 000 habitants in Europe to a total of almost 700 000 people in 2017(Deuschl et al,2020). Transient inflammation and restorable neurological dysfunction often occur during early MS stages, although widespread microglial activation and chronic neurodegeneration gradually develop (Compston and Coles,2008). MS has traditionally been considered an autoimmune disease primarily mediated by CD4 + Th1 cells, but other immune factors likely influence disease progression. SLC1A2 is expressed in astrocytes, neurons, and axonal terminals where it regulates glutamate concentrations in the CNS, often together with SLC1A3. Thus, these two transporters are mechanistically important in preventing excitotoxicity. In the inflammatory CNS microenvironment of MS, SLC1A3 and SLC1A2 levels and glutamate uptake were elevated in optic nerves and reduced excitotoxicity (Vallejo-Illarramendi et al,2006). In cultured astrocytes, SLC1A3 and SLC1A2 levels were reduced after treatment with proinflammatory cytokines (Lee et al,2017). In cortical lesions of MS brains, activated microglia correlated with decreased levels of SLC1A3, SLC1A2 and synaptophysin, and also elevation of phosphorylated (p)-JNK levels in response of excitotoxicity (Vercellino et al,2007). In the inflammation of MS, Th-17 cells function by releasing IL-17A, which promotes glutamate excitotoxicity by decreasing astrocyte SLC1A2, SLC1A3, and glutamine synthetase (GS) expression; and also by stimulating Ca 2+ -dependent glutamate release, indicating an association between inflammation and neurodegeneration in MS (Kostic et al,2017).
In the early stages of neuroinflammation, glutamate released by activated microglia stimulated an increase in extracellular and intracellular glutamate levels of astrocytes and in turn, resulted in reduced astrocytic SLC1A3 levels and failure of extracellular glutamate clearance (Takaki et al,2012). SLC1A3 was also upregulated in the hypothalamus of long-living growth hormone receptor (GHR)-KO mice, together with higher expression of hypothalamic NF-κB, IGF-1 receptor, and the GluA1 subunit of the glutamate receptor, AMPAR expression, and lower IL-1β in many brain regions, these data support the importance of decreased brain inflammation in early adulthood and maintained homeostasis of the glutamatergic and inflammatory systems in extended longevity (Hascup et al,2016). In the brain, SLC7A11 participates in glutamate excitotoxicity, mainly by controlling extracellular nonsynaptic glutamate concentration. Upon SLC7A11 upregulation by immune activation, extracellular glutamate rose and led to excitotoxicity (Pampliega et al,2011).
Experimental allergic (autoimmune) encephalomyelitis (EAE) in mice is widely used as a demyelinating model for MS. After EAE induction, mice lacking N-Myc downstream-regulated gene 2 (Ndrg2) maintained more SLC1A3 and SLC1A2, and the inhibitory effect of NDRG2 on EAAT1 expression was dependent on Akt rather than on NF-κB activity (Le et al,2018). SLC1A3 expression can be altered by xenobiotics, and astrocytic SLC1A3 expression was associated with intraperitoneal injection of a synthetic Toll-like receptor (TLR)-3 ligand, polyinosinic acid, which also promoted IFN-β transcription in the CNS (Costello and Lynch,2013). Moreover, dietary cocoa stimulated SLC1A3 expression, while suppressing inflammatory cytokine expression during prolonged activation of trigeminal ganglion neurons and glia by complete Freund's adjuvant (Cady et al,2013); while Acrolein, a neurotoxin produced in the brain during ischemic stroke, caused astrocytic inflammation via the NLRP3 inflammasome and downregulation of SLC1A3 (Park et al,2020). Myelin-specific CD4 + Th1 cells stimulated glutamate release by SLC7A11 in microglia, and SLC7A11 inhibition improved the conditions of EAE mice and decreased T cell infiltration into the CNS (Evonuk et al,2015). Additionally, Slc1a1 +/mice have elevated levels of inflammatory cytokines in the brain (Afshari et al,2017), and a Slc1a1 suppressor microRNA (miR-26a) affected the response to IFN-β treatment in MS patients (Potenza et al,2018). While peripheral nerve injury resulted in both upregulation of glucocorticoid receptors and downregulation of SLC1A1, inhibition of glucocorticoid receptors rescues SLC1A1 expression levels, possibly through the NF-κB signaling pathway (Wang et al,2006). Furthermore, 1,25(OH) 2 D 3 regulates both Slc1A1 and lipopolysaccharide (LPS)-binding protein CD14 in human osteoclasts (Tarroni et al,2012).
Increased human endogenous retrovirus (HERV) gene activity occurs in immunologically activated glia, and HERV-W encoded glycoprotein syncytin is upregulated in glial cells within acute demyelinating lesions of MS patients (Antony et al,2004). SLC1A4 was found to be a receptor of the HERV-W envelope protein syncytin-1, which could induce iNOS via old astrocyte specifically induced substance (OASIS), and OASIS suppressed astrocytic SLC1A4 (Antony et al,2007). SLC1A5 was reported to be another syncytin-1 receptor and was highly expressed in human umbilical vein endothelial cells (HUVEC) (Yan et al,2017). Syncytin-1 could be induced by TNF-α via the Wnt/β-catenin pathway in squamous cell carcinoma cells 9 (SCC-9), indicating that the interaction of SLC1A5-syncytin-1 may promote cancerendothelial cell fusion (Yan et al,2017).
SLC1A2 is also relevant to other nervous system disorders. The autoantibody NMO-IgG, a biomarker of neuromyelitis optica, targets the aquaporin 4 (AQP4) water channel on astrocytes (Hinson et al,2008).
SLC1A2 expression levels vary according to changes in AQP4 expression, suggesting that SLC1A2 might form complexes with AQP4, and thus pathologically produced NMO-IgG might cause excitotoxicity via AQP4 binding (Hinson et al,2008). Upregulation of SLC1A2 by an antibiotic, ceftriaxone, was shown to accompany downregulation of pro-inflammatory cytokines in rats with traumatic brain injury (Wei et al,2012), and in amyotrophic lateral sclerosis, a stearyl-norleucinevasoactive intestinal peptide rescued the levels and function of SLC1A2 via suppression of TNF-α and downregulation of NF-κB (Goursaud et al,2015). SLC1A2 was also found to be reduced in brains of Alzheimer's disease (AD) patients. SLC1A2 deprivation in astrocytes resulted in both innate and adaptive immune function failure, with gene expression pattern changes similar to those caused by inflammation and synaptic function changes in AD or aged brains, which has been associated with early-onset deficits in short-term memory; meanwhile, SLC1A2 deprivation in neurons was associated with late-onset deficits in long-term memory (Sharma et al,2019).
The SLC1A family also plays a key role in chronic pain, and arachidonic acid is a critical regulator of inflammatory pathways that increases pain sensitivity after nerve injury by activating inflammatory pathways and affecting microglia and astrocytes.The expression/activity of the glutamate transporter in the middle of the synaptic cleft leads to a sustained increase in the concentration of glutamate in and/or around the synaptic cleft, ultimately leading to the continued development of neuropathic pain(Gegelashvili and Bjerrum,2019).

SLCs during infection
Several studies suggested that SLC1A2 participates in viral infections, primarily in the CNS.

Inflammatory macrophage activation during human immunodeficiency virus (HIV) infection caused CNS
symptoms and was associated with glutamate excitotoxicity. However, macrophages were less affected by compensatory increased SLC1A2 expression and GS inhibition due to a reduction in glutamate transport during HIV replication, supporting a potential replacement of affected astrocytes (Porcheray et al,2006).
Astrocyte elevated gene-1 (AEG-1) was found to promote HIV-1-associated neuroinflammation via suppression of SLC1A2 and the NF-κB pathway(Vartak- Sharma et al,2014). During HIV-associated neurocognitive disorders, trace amine receptor 1 (TAAR1) negatively regulated SLC1A2 expression and glutamate uptake, and TAAR1 disruption prevented the decrease in SLC1A2 mediated by methamphetamine, a TAAR1 agonist (Cisneros and Ghorpade,2014). Japanese encephalitis virus (JEV) infection in neurons caused astrogliosis, and elevated SLC1A3 and SLC1A2 expression to detoxify glutamate, and induced other neuroprotective changes, which were nonetheless insufficient to overcome neuronal injuries (Mishra et al,2007). In acute flaccid paralysis caused by the West Nile virus (WNV), the immune response to WNV in the spinal cord influenced astrocytic glutamate reuptake, leading to higher extracellular glutamate and thus, cells without direct virus infection were also damaged by excitotoxicity (Blakely et al,2009 (Williams et al,2007). SLC7A11 was identified as a receptor for Kaposi's sarcoma-associated herpesvirus (KSHV), promoting cell fusion and virion entry of the virus (Kaleeba and Berger,2006). In primary effusion lymphoma (PEL) caused by KSHV, targeting SLC7A11 promoted apoptosis of PEL cells, and inhibitors of SLC7A11 or downstream genes were potential therapeutic targets (Dai et al,2015).

SLCs transporters have also been studied during bacterial infection. Inflammation in astrocytes could
weaken gap junctions, and in the short term, hemichannel activity adjacent to Staphylococcus aureus- The impact of SLCs during parasitic and helminth infections is less known, but BALB-C mice, which are more susceptible to Leishmania major infection, showed higher Slc7a2 expression in macrophages after IFN-γ or IL-4 treatment; and increased arginine might favor the growth of Leishmania major (Sans-Fons et al,2013).

SLCs in other chronic or autoimmune diseases
SLCs have also been implicated in numerous other chronic inflammatory or autoimmunity diseases.
Inflammatory bowel disease (IBD) mainly includes two distinct clinical conditions; Crohn's disease (CD) and ulcerative colitis (UC), and is thought to be caused by an abnormally activated immune response to normal luminal flora (Podolsky,2002). Activating transcription factor 4 (ATF4) was downregulated in This article has not been copyedited and formatted. The final version may differ from this version. inflamed intestinal mucosa of IBD patients, while Slc1a5 transcription was suppressed by ATF4 deficiency in mice, leading to lower glutamine uptake and antimicrobial peptide synthesis in intestinal epithelial cells (Hu et al,2019). During active UC, tissue SLC7A2 and ARG1 expression levels, and arginine concentration were decreased, while NOS2, ARG2 expression were higher (Coburn et al,2016).
Citrobacter rodentium is a widely used mouse model for human intestinal diseases including IBD.
Arginine transporters are involved in conditions such as infections and IBD. In mice, Slc7a2 expression is upregulated in colitis tissues after Citrobacter rodentium infection, and Slc7a2 knockout weakened the immune response and attachment of C. rodentium to the epithelium (Singh et al,2016). Another study showed that elevated arginine levels in the mouse colon at the peak of C. rodentium infection was correlated with downregulation of host Slc7a2 and upregulation of C. rodentium virulence gene expression, indicating that the balance between host and pathogen was affected by arginine(Menezes-Garcia et al,2020).
SLC1A3 and SLC1A2 are also enriched in the joints of the osteoarthritis (OA) rabbit model, resulting in higher concentrations of glutamate and aspartate (Hascup et al,2016). In addition, in the rat retinal Müller cell line rMC-1 induced by high glucose, lower GS and SLC1A3 levels led to higher glutamate levels, and higher IL-17A production, IL-17 receptor A, GFAP, VEGF expression, indicating involvement of SLC1A3 in diabetic retinopathy, a complication of autoimmune diabetes (Qiu et al,2017). During

psoriasis, CD69 in skin γδ T cells altered aryl hydrocarbon receptor (AhR)-dependent IL-22 secretion and
This article has not been copyedited and formatted. The final version may differ from this version. skin inflammation via its regulatory effect on surface expression of SLC7A5-CD98, L-tryptophan uptake and tryptophan-derived AhR activators (Cibrian et al,2016). Finally, in the murine lung during asthma, Arg1 deficiency improved the function and adaptive regulation of Slc7a1 together with Arg2, Nos2, Slc7a7, Ccl2, Ccl11, Tnfɑ, and Ifnɣ, but failed to relieve airway inflammation (Zhu et al,2021). Slc7a1 expression was also upregulated in mammary alveolar epithelial cells (AEC) by LPS stimulation in mouse mammary glands (Kobayashi et al,2013).

SLC-targeted therapeutics and conclusion
Over the past decades, a number of inhibitors targeting SLC1 and SLC7 transporters (Table 2) and many SLC-targeted therapeutics have been developed. However, for SLC1 and SLC7 family transporters only one Riluzole (SLC1A3) has been approved for the treatment of amyotrophic lateral sclerosis (Lin et al,2015). Nonetheless, several preclinical studies suggest SLC-targeted therapeutics against cancer and MS. In breast tumors enriched with cancer stem cells (CSC), targeting SLC7A11 could stimulate immune response and improve chemotherapy sensitivity (Ruiu et al,2019), leading to the development of a viruslike-particle immunotherapeutic approach to target SLC7A11 protein (Bolli et al,2018). Furthermore, SLC7A1 expression was enhanced in a arginine starvation model that mimics an important tumor immune evasion mechanism. Under arginine deprivation SLC7A1 inhibition resulted in arginine uptake and cellular proliferation blockade of T cells (Werner et al,2016). In addition, since arginine synthesis was blocked and SLC7A1 was the only arginine transporter expressed in chronic lymphocytic leukemia (CLL) cells, SLC7A1 inhibition may represent a promising CLL treatment (Werner et al,2019). Slc7a5 was also overexpressed in T cell malignancies, and its inhibitor JPH203 showed an anti-tumor effect (Rosilio et al,2015).
Several agents have been proposed as potential MS therapies that rescue SLC1A3 and SLC1A2 expression. Matrine, a natural quinolizidine alkaloid, showed beneficial effects on inflammation and demyelination in EAE mice by lowering glutamate and increasing SLC1A3 and SLC1A2 expression and GABA concentrations in the brain (Kan et al,2014). EAE mice treated with the immunosuppressive MS This article has not been copyedited and formatted. The final version may differ from this version. medication, fingolimod, exhibited less inflammation mediated by T cells and macrophages/microglia, less astrocyte activation, and restored SLC1A3, SLC1A2 levels in the inflamed spinal cord, potentially via an indirect mechanism (Lee et al,2017). Similarly, In LPS-stimulated astrocytes, disruption of GluA2, a subunit of glutamate receptor AMPAR, by an interfering peptide rescued the expression levels of SLC1A3, SLC1A2, and relieved the MS symptoms of EAE mice (Lee et al,2018). Besides matrine and fingolimod, we found three agonists of SLC1A2. The first one is LDN-212320, which can increase the level of SLC1A2 protein in astrocytes (Xing et al,2011); the second is GPI-1046, which is an antibioticfree immunoavidin ligand that reduces ethanol intake by upregulating SLC1A2 in the PFC and NAc cores (Sari and Sreemantula,2012); the last one is GT 949, which enhances glutamate transport with an EC50 of 0.26 ± 0.03 nM. GT 949 also demonstrates selectivity to SLC1A2 and has no effect on glutamate activity mediated by SLC1A3 or SLC1A1 (Kortagere et al,2018). and IL-1β-induced PI3K/AKT/mTOR pathway in psoriasis (Cibrian et al,2020). And for neurological disease, astrocytes have high transport capacity and affinity for the SLC7A5 substrate [14C]-L-leucine, followed by neurons and microglia, hence such prodrug can use Lat1 for cellular uptake with much higher activity than one of its parent drugs (Huttunen et al,2019).

In obese patients, a population of T cells called mucosal-associated invariant T (MAIT
Currently, there are no reports on the gene polymorphisms (SNPS) of SLC1 and SLC7 family members directly in inflammatory and autoimmune diseases. The diseases related to SLC1 family SNPs were mainly obsessive-compulsive disorder, schizophrenia, epilepsy, essential tremor, stress depression and multiple system atrophy (Gadow et al,2010, Ghosh et al,2020, Jimenez-Jimenez et al,2015, Ritter et al,2016, Soma et al,2008, Wendland et al,2009, Yu et al,2018. The SLC7 family is mostly associated with susceptibility to leprosy, multiple myeloma, schizophrenia and tuberculosis (Cai et al,2018, Poi et al,2019, Wang et al,2020b, Wang et al,2018.
Taken together, SLCs of amino acids, especially SLC1 family members as glutamate transporters and SLC7 members as arginine transporters, play important roles in various conditions involving inflammation and immune responses, such as MS, IBD, viral infections, tumor immunotherapies, and chronic intestinal inflammation via modulating the function of astrocytes, macrophages, and T cells.
Further studies should focus on determining the specific mechanism of these SLCs in regulating immune functions and course of diseases, developing specific inhibitors as potential therapy for these diseases, or characterizing the numerous SLCs that still remain to be studied.

Authorship Contributions
Participated in research design: Ligong Chen.
Performed data analysis: Linlin Sheng and Qi Luo.
Wrote or contributed to the writing of the manuscript: Ligong Chen, Linlin Sheng and Qi Luo.
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