Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions.
Robert Haas,Joanne Smith,Vidalba Rocher-Ros,Suchita Nadkarni,Trinidad Montero-Melendez,Fulvio D'Acquisto,Elliot James Bland,Michele Bombardieri,Costantino Pitzalis,Mauro Perretti,Federica M. Marelli-Berg,Claudio Mauro +11 more
TLDR
A novel role of lactate is established in control of proinflammatory T cell motility and effector functions, which provides 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.Abstract:
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.read more
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Fundamentals of cancer metabolism
TL;DR: A conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis will progressively support the development of new strategies to treat human cancer.
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LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.
Almut Brand,Katrin Singer,Gudrun E. Koehl,Marlene Kolitzus,Gabriele Schoenhammer,Annette Thiel,Carina Matos,Christina Bruss,Sebastian Klobuch,K. Peter,K. Peter,Michael Kastenberger,Christian Bogdan,Ulrike Schleicher,Andreas Mackensen,Evelyn Ullrich,Stefan Fichtner-Feigl,Stefan Fichtner-Feigl,Rebecca Kesselring,Matthias Mack,Matthias Mack,Uwe Ritter,Maximilian Schmid,Maximilian Schmid,Christian U. Blank,Katja Dettmer,Peter J. Oefner,Petra Hoffmann,Petra Hoffmann,Stefan Walenta,E. K. Geissler,Jacques Pouysségur,Andreas Villunger,André Steven,Barbara Seliger,Stephan Schreml,Sebastian Haferkamp,Elisabeth Kohl,Sigrid Karrer,Mark Berneburg,Wolfgang Herr,Wolfgang Mueller-Klieser,Kathrin Renner,Kathrin Renner,Marina Kreutz,Marina Kreutz +45 more
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Metabolic Instruction of Immunity
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Macrophages and Metabolism in the Tumor Microenvironment
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Lactate in the brain: from metabolic end-product to signalling molecule
TL;DR: Overall, lactate ensures adequate energy supply, modulates neuronal excitability levels and regulates adaptive functions in order to set the 'homeostatic tone' of the nervous system.
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Cancer Cell Metabolism: Warburg and Beyond
TL;DR: The Warburg effect of aerobic glycolysis is re-examine and a framework for understanding its contribution to the altered metabolism of cancer cells is established.
Journal ArticleDOI
Functional polarization of tumour-associated macrophages by tumour-derived lactic acid
Oscar R. Colegio,Ngoc Quynh Chu,Alison L. Szabo,Thach Chu,Anne Marie Rhebergen,Vikram Jairam,Nika Cyrus,Carolyn Brokowski,Stephanie C. Eisenbarth,Gillian M. Phillips,Gary W. Cline,Andrew J. Phillips,Ruslan Medzhitov +12 more
TL;DR: It is shown that lactic acid produced by tumour cells, as a by-product of aerobic or anaerobic glycolysis, has a critical function in signalling, through inducing the expression of vascular endothelial growth factor and the M2-like polarization of tumour-associated macrophages and this effect is mediated by hypoxia-inducible factor 1α (HIF1α).
Journal ArticleDOI
Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
Chih-Hao Chang,Jonathan D. Curtis,Leonard B. Maggi,Brandon Faubert,Alejandro V. Villarino,David O’Sullivan,Stanley Ching-Cheng Huang,Gerritje J.W. van der Windt,Julianna Blagih,Jing Qiu,Jason D. Weber,Edward J. Pearce,Russell G. Jones,Erika L. Pearce +13 more
TL;DR: It is shown here that aerobic glycolysis is specifically required for effector function in T cells but that this pathway is not necessary for proliferation or survival.