Background RA is a systemic-autoimmune-disease characterized by chronic inflammation of the synovial-joints. Up to 30–40% of patients do not respond to treatment and current biomarkers are largely insensitive at predicting disease progression and response to treatment. It is well recognised that RA-synovitis is a heterogeneous pathology with different histological phenotypes i.e. lymphoid-(L), myeloid-(M) and fibroid-(F). As a result of inflammation the RA synovial microenvironment is hypoxic and acidic partly due to the accumulation of lactate, the end product of anaerobic glycolysis. Exposure of CD4+ T cells to lactate inhibits their migratory capabilities and induces their shift toward a Th17 phenotype1,2. These effects are mediated via the interaction of lactate with its transporter SLC5A12, which is expressed on the CD4+ T cell surface1,2.
Objectives To characterize whether the newly identified lactate/SLC5A12-induced metabolic signalling pathway can be harnessed in the stratification of RA patients in the different histological phenotypes and to modulate inflammatory responses in vitro and in vivo.
Methods RA peripheral blood cells, RA synovial tissues (ST, 21 lymphoid and 8 myeloid) and mononuclear cells from tonsil of patients undergoing tonsillectomy were included in the analysis. RNA sequencing of RA-ST was performed and data analysed for the expression of metabolic genes. SLC5A12 expression and IL17 production was performed by flow-cytometry. Cytokines and transcription factors mRNA relative expression was evaluated by RT-PCR. Seahorse and western blot analysis was performed for the evaluation of metabolic pathways. Transwell plates were used for migration assays. Human-glucose-6-phosphate-isomerase (hG6PI) induced arthritis model was used to evaluate the impact of anti-SLC5A12 on the clinical and histological score.
Results We showed that: i) the expression of SLC5A12 is up-regulated by CD4+ T cells upon inflammation; ii) SLC5A12 is up-regulated in anti-CD3 stimulated RA CD4+ T cells cultured in autologous synovial fluid; iii) the lactate/SLC5A12 induced metabolic pathway is differentially activated in RA patients with distinctive synovial “pathotypes”; iv) SLC5A12 antibody reduces lactate-induced pro-inflammatory cytokines, limits Th17 and follicular helper T cell differentiation, reverses lactate impaired CD4+ T cell migration and restores lactate-mediated inhibition of glycolysis in vitro; v) antibody-mediated blockade of SLC5A12 ameliorates the clinical course in human-glucose-6-phosphate-isomerase (hG6PI)-induced arthritis.
Conclusions Targeting lactate/SLC5A12-induced metabolic signalling pathway may provide a novel therapeutic strategy to reduce inflammation in RA patients.
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Acknowledgements This work is supported by a fellowship from the Arthritis Research UK (ARUK) to V.P. by a fellowship from the British Heart Foundation, a project grant from the CARIPLO Foundation, a Proof of Concept award from Queen Mary Inno-vation, Ltd., to C.M. and MRC ARUK founded project “The Pathobiology of Early Arthritis Cohort (PEAC)” to C.P.
Disclosure of Interest None declared