| First Author | Noe JT | Year | 2021 |
| Journal | Sci Adv | Volume | 7 |
| Issue | 46 | Pages | eabi8602 |
| PubMed ID | 34767443 | Mgi Jnum | J:320259 |
| Mgi Id | MGI:6826918 | Doi | 10.1126/sciadv.abi8602 |
| Citation | Noe JT, et al. (2021) Lactate supports a metabolic-epigenetic link in macrophage polarization. Sci Adv 7(46):eabi8602 |
| abstractText | 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. |
