Abstract
SummaryAccumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4+ T cells. SLC5A12-mediated lactate uptake into CD4+ T cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4+ T cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Finally, we propose that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders.
Highlights
The recent discovery of the fundamental role of metabolism in immune cell biology is contributing immensely to our understanding of immune cell regulation (Buck et al, 2016; O’Neill et al, 2016).So far, most studies have focused on the role of metabolic pathways in the establishment of the immune response
We found that CD4+ T cells from Rheumatoid arthritis (RA) SFMCs presented high levels of SLC5A12 irrespective of any activating or inflammatory stimuli we used ex vivo, as compared to CD4+ T cells from RA peripheral blood mononuclear cells (PBMCs) activated in the presence of autologous blood serum (BS), suggesting they have already experienced maximal levels of SLC5A12 inducing factors, i.e., antigen and exposure to inflammatory cues (Figure 1G)
Data expressed as mean ± SEM. *p % 0.05; **p % 0.01; ***p % 0.001; ###p % 0.001 versus lactate (H). (J) Schematic depicting the described findings: lactate modulates IL17 expression by activating two pathways, pyruvate kinase M2 (PKM2) translocation into the nucleus and fatty acid synthesis (FAS) induction, converging on signal transducer and activator of transcription 3 (STAT3)-induced transcription of IL17
Summary
The recent discovery of the fundamental role of metabolism in immune cell biology is contributing immensely to our understanding of immune cell regulation (Buck et al, 2016; O’Neill et al, 2016).So far, most studies have focused on the role of metabolic pathways in the establishment of the immune response. Novel signaling functions of metabolic intermediates in the regulation of immunity, including the small metabolites lactate, acetyl-CoA, succinate, itaconate, and others have been revealed. They report on a mechanism that involves a transporter known as SLC5A12, which brings lactate into the cell. This transporter is expressed by a specific subset of lymphocytes, the CD4+ T cells, often infiltrating the inflamed tissues. They discover that SLC5A12-driven lactate uptake leads to a stepwise reprogramming of cellular metabolism, which supports a pro-inflammatory response by CD4+ T cells. Targeting SLC5A12 pharmacologically with a monoclonal antibody shows promising results in a pre-clinical model of rheumatoid arthritis characterized by the infiltration of CD4+ T cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
