Lactate supports a metabolic-epigenetic link in macrophage polarization.

Autor: Noe JT; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, USA.; J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA., Rendon BE; J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA., Geller AE; J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.; Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA., Conroy LR; Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA.; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA., Morrissey SM; J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.; Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA., Young LEA; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA., Bruntz RC; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA., Kim EJ; J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA., Wise-Mitchell A; J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA., Barbosa de Souza Rizzo M; J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA., Relich ER; Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA., Baby BV; J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA., Johnson LA; Department of Physiology, University of Kentucky, Lexington, KY 40536, USA.; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40356, USA., Affronti HC; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA., McMasters KM; J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.; Division of Immunotherapy, Department of Surgery, University of Louisville, Louisville, KY 40202, USA., Clem BF; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, USA.; J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA., Gentry MS; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA., Yan J; J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.; Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA.; Division of Immunotherapy, Department of Surgery, University of Louisville, Louisville, KY 40202, USA., Wellen KE; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA., Sun RC; Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA.; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40356, USA., Mitchell RA; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, USA.; J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.; Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA.; Division of Immunotherapy, Department of Surgery, University of Louisville, Louisville, KY 40202, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2021 Nov 12; Vol. 7 (46), pp. eabi8602. Date of Electronic Publication: 2021 Nov 12.
DOI: 10.1126/sciadv.abi8602
Abstrakt: 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.
Databáze: MEDLINE