Lactate supports a metabolic-epigenetic link in macrophage polarization

Lactate accumulation is a hallmark of solid cancers and is linked to the immune suppressive phenotypes of tumor-infiltrating immune cells. We report herein that interleukin-4 (IL-4)–induced M0 → M2 macrophage polarization is accompanied by interchangeable glucose- or lactate-dependent tricarboxylic...

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Bibliographic Details
Published in:	Science advances Vol. 7; no. 46; p. eabi8602
Main Authors:	Noe, Jordan T, Rendon, Beatriz E, Geller, Anne E, Conroy, Lindsey R, Morrissey, Samantha M, Young, Lyndsay E A, Bruntz, Ronald C, Kim, Eun J, Wise-Mitchell, Ashley, Barbosa de Souza Rizzo, Mariana, Relich, Eric R, Baby, Becca V, Johnson, Lance A, Affronti, Hayley C, McMasters, Kelly M, Clem, Brian F, Gentry, Matthew S, Yan, Jun, Wellen, Kathryn E, Sun, Ramon C, Mitchell, Robert A
Format:	Journal Article
Language:	English
Published:	United States American Association for the Advancement of Science 12-11-2021
Subjects:	Biomedicine and Life Sciences Cancer Immunology SciAdv r-articles
Online Access:	Get full text
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Summary:	Lactate accumulation is a hallmark of solid cancers and is linked to the immune suppressive phenotypes of tumor-infiltrating immune cells. We report herein that interleukin-4 (IL-4)–induced M0 → M2 macrophage polarization is accompanied by interchangeable glucose- or lactate-dependent tricarboxylic acid (TCA) cycle metabolism that directly drives histone acetylation, M2 gene transcription, and functional immune suppression. Lactate-dependent M0 → M2 polarization requires both mitochondrial pyruvate uptake and adenosine triphosphate–citrate lyase (ACLY) enzymatic activity. Notably, exogenous acetate rescues defective M2 polarization and histone acetylation following mitochondrial pyruvate carrier 1 (MPC1) inhibition or ACLY deficiency. Lastly, M2 macrophage–dependent tumor progression is impaired by conditional macrophage ACLY deficiency, further supporting a dominant role for glucose/lactate mitochondrial metabolism and histone acetylation in driving immune evasion. This work adds to our understanding of how mitochondrial metabolism affects macrophage functional phenotypes and identifies a unique tumor microenvironment (TME)–driven metabolic-epigenetic link in M2 macrophages.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2375-2548 2375-2548
DOI:	10.1126/sciadv.abi8602