ArticleProceedings of the National Academy of Sciences of the United States of America2021
SLC15A4 mediates M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28 citing papers in PubMed, 48 citations in OpenAlex.
- The Pharmacology of the SLC15A4-TASL Complex, an Emerging Target for the Treatment of Lupus.Pharmacology research & perspectives · 2026Review
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- Understanding Sex Differences in Autoimmune Diseases: Immunologic Mechanisms.International journal of molecular sciences · 2025Review
- Pattern recognition receptors: function, regulation and therapeutic potential.Signal transduction and targeted therapy · 2025Review
- Immunometabolism in systemic lupus erythematosus.Nature reviews. Rheumatology · 2025Review
- Lysosomal Ion Channels and Transporters: Recent Findings, Therapeutic Potential, and Technical Approaches.Bioelectricity · 2025Review
- Selenoproteome depletion enhances oxidative stress and alters neutrophil functions in Citrobacter rodentium infection leading to gastrointestinal inflammation.Free radical biology & medicine · 2025Article
- The TLR7/9 adaptors TASL and TASL2 mediate IRF5-dependent antiviral responses and autoimmunity in mouse.Nature communications · 2025Article
- Article
- New approaches to the control of chronic inflammatory diseases with a focus on the endolysosomal system of immune cells.International immunology · 2024Review
- Chemoproteomic development of SLC15A4 inhibitors with anti-inflammatory activity.Nature chemical biology · 2024Article
- Regulation of macrophage polarization by targeted metabolic reprogramming for the treatment of lupus nephritis.Molecular medicine (Cambridge, Mass.) · 2024Review
- Article
- The ubiquitin-proteasome system in the tumor immune microenvironment: a key force in combination therapy.Frontiers in immunology · 2024Review
- Oligopeptide/Histidine Transporter PHT1 and PHT2 - Function, Regulation, and Pathophysiological Implications Specifically in Immunoregulation.Pharmaceutical research · 2023Review
- Review
- Polyphenol-rich diet mediates interplay between macrophage-neutrophil and gut microbiota to alleviate intestinal inflammation.Cell death & disease · 2023Article
- Article
- M2 Macrophage-Derived sEV Regulate Pro-Inflammatory CCR2Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Metabolic control from the endolysosome: lysosome-resident amino acid transporters open novel therapeutic possibilities.Frontiers in immunology · 2023Review
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Authors and funding
17 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The amino acid and oligopeptide transporter Solute carrier family 15 member A4 (SLC15A4), which resides in lysosomes and is preferentially expressed in immune cells, plays critical roles in the pathogenesis of lupus and colitis in murine models. Toll-like receptor (TLR)7/9- and nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-mediated inflammatory responses require SLC15A4 function for regulating the mechanistic target of rapamycin complex 1 (mTORC1) or transporting L-Ala-γ-D-Glu-meso-diaminopimelic acid, IL-12: interleukin-12 (Tri-DAP), respectively. Here, we further investigated the mechanism of how SLC15A4 directs inflammatory responses. Proximity-dependent biotin identification revealed glycolysis as highly enriched gene ontology terms. Fluxome analyses in macrophages indicated that SLC15A4 loss causes insufficient biotransformation of pyruvate to the tricarboxylic acid cycle, while increasing glutaminolysis to the cycle. Furthermore, SLC15A4 was required for M1-prone metabolic change and inflammatory IL-12 cytokine productions after TLR9 stimulation. SLC15A4 could be in close proximity to AMP-activated protein kinase (AMPK) and mTOR, and SLC15A4 deficiency impaired TLR-mediated AMPK activation. Interestingly, SLC15A4-intact but not SLC15A4-deficient macrophages became resistant to fluctuations in environmental nutrient levels by limiting the use of the glutamine source; thus, SLC15A4 was critical for macrophage's respiratory homeostasis. Our findings reveal a mechanism of metabolic regulation in which an amino acid transporter acts as a gatekeeper that protects immune cells' ability to acquire an M1-prone metabolic phenotype in inflammatory tissues by mitigating metabolic stress.
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