SLC7A7 Transporter Fuels Macrophage Repair Programs That Slow Artery Disease

Atherosclerosis — the leading cause of heart attack and stroke — is driven partly by dysfunctional macrophages trapped in arterial plaques that fail to clear dead cells and resolve inflammation. Macrophage metabolism is increasingly recognized as a master regulator of these failure modes, but the molecular machinery governing amino acid fuel use in living plaques has remained poorly understood.

This study systematically dissected the roles of two glutaminase isoforms (GLS1 and GLS2), glutamine synthetase (GS), and a family of solute carrier transporters in macrophage metabolic reprogramming. Using human carotid plaque transcriptomics, bone-marrow transplant atherosclerosis models in Ldlr−/− mice, and extensive in vitro BMDM assays, the authors showed that GLS2 expression does not differ between stable and unstable human plaques and that germline Gls2 knockout — alone or combined with myeloid Gls1 deletion — neither impairs macrophage restorative functions nor worsens atherosclerosis. GLS1, not GLS2, is the functionally relevant glutaminase isoform in this disease context.

Glutamine synthetase (encoded by Glul) emerged as a metabolic counterweight to GLS1. IL-4 stimulation suppresses Glul while upregulating Gls1, channeling more glutamate toward oxidative phosphorylation rather than back toward glutamine synthesis. Pharmacological GS inhibition (methionine sulfoximine, MSO) in resting macrophages recapitulated reparative metabolic features — enhanced maximal respiration, increased ATP production, elevated CD206 expression, and improved efferocytosis — but these effects depended on intact GLS1, confirming that GLS1-derived glutamate is the substrate for GS. Under already-reparative (IL-4) conditions where Glul is already repressed, MSO had minimal additional impact.

Critically, the study identified SLC7A7 as the predominant glutamine importer enabling GLS1-dependent glutaminolysis. Slc7a7 silencing reduced intracellular glutamine influx, blunted GLS1 activity, and impaired downstream signaling involved in macrophage restorative programs. Macrophage-specific Slc7a7 deletion in vivo accelerated atherosclerotic plaque development and produced more complex necrotic core composition, closely mirroring the phenotype of myeloid Gls1 deficiency. Transcriptomic analyses revealed that SLC7A7-dependent glutamine flux orchestrates broad metabolic and transcriptional rewiring, balancing plaque remodeling against restorative macrophage identity.

These findings establish a linear axis — SLC7A7 → glutamine influx → GLS1-dependent glutaminolysis → ATP and signaling molecules → restorative macrophage functions — as a disease-relevant pathway in atherosclerosis. The work nominates SLC7A7 as a potential therapeutic target for boosting macrophage repair capacity in cardiovascular disease, while cautioning that GLS2 and GS inhibition have context-dependent and sometimes opposing effects that would need careful consideration in any therapeutic strategy.