The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions
Open accessAbstract
Lactate has long been considered a "waste" by-product of cell metabolism, and it accumulates at sites of inflammation. Recent findings have identified lactate as an active metabolite in cell signalling, although its effects on immune cells during inflammation are largely unexplored. Here we ask whether lactate is responsible for T cells remaining entrapped in inflammatory sites, where they perpetuate the chronic inflammatory process. We show that lactate accumulates in the synovia of rheumatoid arthritis patients. Extracellular sodium lactate and lactic acid inhibit the motility of CD4+ and CD8+ T cells, respectively. This selective control of T cell motility is mediated via subtype-specific transporters (Slc5a12 and Slc16a1) that we find selectively expressed by CD4+ and CD8+ subsets, respectively. We further show both in vitro and in vivo that the sodium lactate-mediated inhibition of CD4+ T cell motility is due to an interference with glycolysis activated upon engagement of the chemokine receptor CXCR3 with the chemokine CXCL10. In contrast, we find the lactic acid effect on CD8+ T cell motility to be independent of glycolysis control. In CD4+ T helper cells, sodium lactate also induces a switch towards the Th17 subset that produces large amounts of the proinflammatory cytokine IL-17, whereas in CD8+ T cells, lactic acid causes the loss of their cytolytic function. We further show that the expression of lactate transporters correlates with the clinical T cell score in the synovia of rheumatoid arthritis patients. Finally, pharmacological or antibody-mediated blockade of subtype-specific lactate transporters on T cells results in their release from the inflammatory site in an in vivo model of peritonitis. By establishing a novel role of lactate in control of proinflammatory T cell motility and effector functions, our findings provide a potential molecular mechanism for T cell entrapment and functional changes in inflammatory sites that drive chronic inflammation and offer targeted therapeutic interventions for the treatment of chronic inflammatory disorders.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837
Differentiation of Effector CD4 T Cell Populations
Zhu, J., Yamane, H., & Paul, W. E. (2010) · Annual Review of Immunology · doi:10.1146/annurev-immunol-030409-101212 · Cited by 3,452
Functional Polarization of Tumour-Associated Macrophages by Tumour-Derived Lactic Acid
Colegio, O. R., Chu, N.-Q., Szabo, A. L., Chu, T., Rhebergen, A. M., Jairam, V., Cyrus, N., Brokowski, C. E., Eisenbarth, S. C., Phillips, G. M., et al. (2014) · Nature · doi:10.1038/nature13490 · Cited by 3,046
Cancer cell metabolism: warburg and beyond
Hsu, P. P., & Sabatini, D. M. (2008) · Cell · doi:10.1016/j.cell.2008.08.021 · Cited by 2,452
Michalek, R. D., Gerriets, V. A., Jacobs, S. R., Macintyre, A. N., MacIver, N. J., Mason, E. F., Sullivan, S. A., Nichols, A. G., & Rathmell, J. C. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003613 · Cited by 2,091
Shi, L. Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D. R., & Chi, H. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20110278 · Cited by 1,803
Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells
Kleinewietfeld, M., Manzel, A., Titze, J., Kvakan, H., Yosef, N., Linker, R. A., Muller, D. N., & Hafler, D. A. (2013) · Nature · doi:10.1038/nature11868 · Cited by 1,394
Biochemistry of exercise-induced metabolic acidosis
Robergs, R. A., Ghiasvand, F., & Parker, D. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00114.2004 · Cited by 1,304
Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function
Sukumar, M., Liu, J., Ji, Y., Subramanian, M., Crompton, J. G., Yu, Z., Roychoudhuri, R., Palmer, D. C., Muranski, P., Karoly, E. D., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69589 · Cited by 952
Végran, F., Boidot, R., Michiels, C., Sonveaux, P., & Feron, O. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-2828 · Cited by 816
Ene–Obong, A., Clear, A. J., Watt, J., Wang, J., Fatah, R., Riches, J. C., Marshall, J. F., Chin–Aleong, J., Chelala, C., Gribben, J. G., et al. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.07.025 · Cited by 579
Humby, F., Bombardieri, M., Manzo, A., Kelly, S., Blades, M. C., Kirkham, B., Spencer, J., & Pitzalis, C. (2009) · PLoS Medicine · doi:10.1371/journal.pmed.0060001 · Cited by 537
Self-citation
Cited by
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells
Brand, A., Singer, K., Koehl, G. E., Kolitzus, M., Schoenhammer, G., Thiel, A., Matos, C., Bruss, C., Klobuch, S., Peter, K., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.011 · Cited by 2,039
Macrophages and metabolism in the tumor microenvironment
Vitale, I., Manic, G., Coussens, L. M., Kroemer, G., & Galluzzi, L. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.06.001 · Cited by 1,837
Lactate metabolism in human health and disease
Li, X., Yang, Y., Zhang, B., Lin, X., Fu, X., An, Y., Zou, Y., Wang, J.-X., Wang, Z., & Yu, T. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01151-3 · Cited by 1,454
Lactate in the brain: from metabolic end-product to signalling molecule
Magistretti, P. J., & Allaman, I. (2018) · Nature Reviews Neuroscience · doi:10.1038/nrn.2018.19 · Cited by 1,298
Metadata
- Authors
- Haas, R., Smith, J., Rocher-Ros, V., Nadkarni, S., Montero-Melendez, T., D’Acquisto, F., Bland, E. J., Bombardieri, M., Pitzalis, C., Perretti, M., Marelli-Berg, F. M., & Mauro, C.
- Venue
- PLOS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-07-16
- Volume
- 13
- Issue
- 7
- Pages
- e1002202
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- OpenAlex
- W900373682
- Cited by
- 774
- References
- 13
- FWCI
- 12.78
- Type
- journal article
- Language
- en
- Open access
- gold
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
