Lactate signalling leads to aggregation of immune-inflammatory hotspots and SLC5A12 blockade promotes their resolution
Ectopic lymphoid structures (ELS) are aggregates of lymphoid cells that often form within inflamed tissues in patients with autoimmune diseases, cancer, infectious diseases and cardiovascular conditions. These structures drive B cell maturation into memory B cells and plasma cells through B cell and T cell co-stimulation, and their role in pathogenesis is increasingly recognized. Understanding how ELS develop and persist in inflamed tissues is essential for elucidating the pathogenesis and treatment responses in diseases in which they have a prominent role. Here we show that metabolic pathways and specific metabolites, in particular lactate, are master regulators of ELS organization in Sjögren's disease (SjD), the second-most common autoimmune rheumatic disease. Furthermore, inhibiting lactate uptake by lactate transporters, specifically by SLC5A12 blockade, represents a previously unappreciated checkpoint in autoimmune inflammatory diseases. This approach results in multidimensional pro-resolution effects, including reduced inflammatory cytokine levels, enhanced T cell egress from inflamed sites and diminished T cell and B cell areas and their segregation within ELS.
Authors
- Benjamin A. Fisher (ORCID: https://orcid.org/0000-0003-4631-549X)
- Jason D. Turner (ORCID: https://orcid.org/0000-0002-5423-5302)
- Fabian Spill (ORCID: https://orcid.org/0000-0001-8462-5080)
- Daria Apostolo (ORCID: https://orcid.org/0000-0002-2416-7468)
- Claudio Mauro (ORCID: https://orcid.org/0000-0002-3736-0099)
- Ronny Schmidt (ORCID: https://orcid.org/0009-0002-5173-8649)
- Davide Lucchesi (ORCID: https://orcid.org/0000-0002-8019-556X)
- Serena Colafrancesco (ORCID: https://orcid.org/0000-0001-7802-1192)
- Elena Pontarini (ORCID: https://orcid.org/0000-0003-0439-0344)
- Giulia Cavallaro (ORCID: https://orcid.org/0009-0000-1212-8368)
- Michelangelo Certo
- Christoph Schröder (ORCID: https://orcid.org/0000-0001-6177-1042)
- Joana Campos (ORCID: https://orcid.org/0000-0001-8119-7607)
- Saba Nayar (ORCID: https://orcid.org/0000-0002-4350-110X)
- Stefano Bombardieri (ORCID: https://orcid.org/0000-0002-3878-5216)
- S G Gilbert (ORCID: https://orcid.org/0000-0002-7502-8409)
- Charlotte G. Smith
Institutions
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- University Hospitals Birmingham NHS Foundation Trust (GB)
- Humanitas University (IT)
- Queen Mary University of London (GB)
- University of Catania (IT)
- County Hospital (GB)
- William Harvey Research Institute (GB)
- Centre for Inflammation Research (GB)
- NIHR Birmingham Biomedical Research Centre (GB)
- IRCCS Humanitas Research Hospital (IT)
- University of Birmingham (GB)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2025-08-04
- DOI
- https://doi.org/10.1038/s42255-025-01331-9
- Citations
- 4
- Primary Topic
- Diabetes and associated disorders
- Type
- article
- Field-Weighted Citation Impact
- 7.27