Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis
Atherosclerosis is a life-threatening condition characterized by chronic inflammation of the arterial wall. Atherosclerotic plaque macrophages are key players at the site of disease, where metabolic reprogramming dictates the progression of pathogenesis. Here we show that reduced macrophage glutaminase activity is related to glutaminase (GLS)-1 and not GLS2 expression. While glutamine synthetase serves as a metabolic rheostat controlling nutrient flux into cells in vitro, macrophage restorative functions in the context of atherosclerosis relies more heavily on glutamine influx. Enhanced glutamine flux is largely mediated by the SLC7A7 exchanger in macrophages: Slc7a7-silenced macrophages have reduced glutamine influx and GLS1-dependent glutaminolysis, impeding downstream signalling involved in macrophage restorative functions. In vivo, macrophage-specific deletion of Slc7a7 accelerates atherosclerosis in mice with more complex necrotic core composition. Finally, cell-intrinsic regulation of glutaminolysis drives macrophage metabolic and transcriptional rewiring in atherosclerosis by diverting exogenous Gln flux to balance remodelling and restorative functions. Thus, we uncover a role of SLC7A7-dependent glutamine uptake upstream of glutaminolysis in atherosclerotic plaque development and stability.
Authors
- Béatrice Bailly‐Maitre (ORCID: https://orcid.org/0000-0002-8389-8498)
- Nathalie Vaillant
- Emmanuel L. Gautier (ORCID: https://orcid.org/0000-0003-2976-7566)
- Minna Unelma Kaikkonen (ORCID: https://orcid.org/0000-0001-6294-0979)
- Thibault Barouillet (ORCID: https://orcid.org/0009-0006-0157-3523)
- Erik A.L. Biessen (ORCID: https://orcid.org/0000-0002-6454-8548)
- Clément Cochain (ORCID: https://orcid.org/0000-0002-0340-1745)
- Sébastien Dussaud (ORCID: https://orcid.org/0000-0002-5365-8338)
- Edward B. Thorp (ORCID: https://orcid.org/0000-0003-1387-7058)
- Yohan Gerber-Ferder (ORCID: https://orcid.org/0000-0001-9973-2196)
- Manuel Palacı́n (ORCID: https://orcid.org/0000-0002-8670-293X)
- Camille Blériot (ORCID: https://orcid.org/0000-0002-4298-2888)
- Tiit Örd (ORCID: https://orcid.org/0000-0002-3098-1749)
- Laurent Yvan‐Charvet (ORCID: https://orcid.org/0000-0002-7748-4942)
- Florent Ginhoux (ORCID: https://orcid.org/0000-0002-2857-7755)
- Florent Murcy
- Judith C. Sluimer (ORCID: https://orcid.org/0000-0002-0269-4582)
- Susanna Bodoy (ORCID: https://orcid.org/0000-0001-9261-4373)
- Coraline Borowczyk (ORCID: https://orcid.org/0000-0002-0193-6578)
- Marina Blanc (ORCID: https://orcid.org/0009-0006-3656-1282)
- Lama Habbouche
- S. Carmino Benhmammouch
- Clara Pierrot-Blanchet
Institutions
- Northwestern University (US)
- Universitat de Vic - Universitat Central de Catalunya (ES)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- University of Eastern Finland (FI)
- Shanghai Jiao Tong University (CN)
- Université Paris Cité (FR)
- Maastricht University Medical Centre (NL)
- Singapore Immunology Network (SG)
- Institut Gustave Roussy (FR)
- Maastricht University (NL)
- Sorbonne Université (FR)
- Institut Necker Enfants Malades (FR)
- Sorbonne Paris Cité (FR)
- Centre Méditerranéen de Médecine Moléculaire (FR)
- Institute for Research in Biomedicine (ES)
- Universitätsklinikum Würzburg (DE)
- Paris Cardiovascular Research Center (FR)
- Universitat de Barcelona (ES)
- RWTH Aachen University (DE)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2025-09-22
- DOI
- https://doi.org/10.1038/s42255-025-01354-2
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.80