The inflamed synovium in rheumatoid arthritis (RA) contains a high concentration of lactate that has traditionally been thought to be a by-product of synovial fibroblast proliferation. In a new study, researchers describe how lactate can function as an effector molecule by reprogramming CD4+ T cells to a pro-inflammatory phenotype, thereby exacerbating disease in patients with RA who predominantly have lymphoid cell infiltrates in their synovium (the so-called lymphoid pathotype).
“We identified the pathway initiated by lactate build-up in inflamed tissue that exacerbates the tissue inflammatory response in diseases with an important CD4+ T cell component, such as the lymphoid pathotype of RA,” states corresponding author Claudio Mauro. Specifically, the researchers investigated SLC5A12, a sodium-dependent lactate transporter protein that they have previously shown to be expressed on CD4+ T cells, but not CD8+ T cells, in mice. In their new study, the researchers showed that, upon activation with either anti-CD3 antibodies or RA synovial fluid, SLC5A12 was upregulated in peripheral blood CD4+ T cells from patients with RA compared with those from healthy individuals.
Further in vitro and in vivo experiments revealed that lactate was taken up by SLC5A12 in CD4+ T cells, where it induced a switch in metabolism away from glycolysis and towards fatty acid synthesis and PMK2 nuclear activity. These changes in metabolism led to the increased expression of IL-17 by these cells in the presence of lactate. Experiments with synovial tissue explants also revealed a role for SLC5A12 in controlling lactate-induced tissue retention of T cells; blocking SLC5A12 with an antibody enabled the egress of CD4+ T cells from the tissue explants.
lactate was taken up by SLC5A12 in CD4+ T cells, where it induced a switch in metabolism
RNA sequencing of synovial tissue samples from DMARD-naive patients with RA showed a distinct positive correlation between SLC5A12 expression and disease activity. “We also used a murine model of RA that is characterized by CD4+ T cell infiltration in the arthritic joints to mimic the lymphoid pathotype and showed that blocking SLC5A12 improves the clinical signs of disease,” says Mauro. The researchers suggest that SLC5A12 could be a future therapeutic target for the lymphoid pathotype of RA.
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Original article
Pucino, V. et al. Lactate buildup at the site of chronic inflammation promotes disease by inducing CD4+ T cell metabolic rewiring. Cell Metabolism https://doi.org/10.1016/j.cmet.2019.10.004 (2019)
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Clarke, J. Lactate rewires synovial T cells in RA. Nat Rev Rheumatol 16, 4 (2020). https://doi.org/10.1038/s41584-019-0344-1
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DOI: https://doi.org/10.1038/s41584-019-0344-1
