Lactate signalling leads to aggregation of immune-inflammatory hotspots and SLC5A12 blockade promotes their resolution
Certo, Michelangelo Pontarini, Elena Gilbert, Sebastian G Schmidt, Ronny Turner, Jason D Lucchesi, Davide Apostolo, Daria Cavallaro, Giulia Smith, Charlotte G Colafrancesco, Serena
Certo, Michelangelo
Pontarini, Elena
Gilbert, Sebastian G
Schmidt, Ronny
Turner, Jason D
Lucchesi, Davide
Apostolo, Daria
Cavallaro, Giulia
Smith, Charlotte G
Colafrancesco, Serena
Affiliation
University of Birmingham; Queen Mary University of London; Sciomics GmbH; University of Piemonte Orientale; University of Catania; IRCCS Humanitas Research Hospital; Propath UK Limited; University Hospitals Birmingham NHS Foundation Trust
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Publication date
2025-08-04
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Abstract
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.
Citation
Certo M, Pontarini E, Gilbert SG, Schmidt R, Turner JD, Lucchesi D, Apostolo D, Cavallaro G, Smith CG, Colafrancesco S, Campos J, Nayar S, Schröder C, Fisher BA, Spill F, Bombardieri M, Mauro C. Lactate signalling leads to aggregation of immune-inflammatory hotspots and SLC5A12 blockade promotes their resolution. Nat Metab. 2025 Aug;7(8):1663-1680. doi: 10.1038/s42255-025-01331-9. Epub 2025 Aug 4.
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Article