Hypoxia and glycolysis have long been appreciated to promote immune cell activation. In 2019, several studies highlighted a counterbalancing homeostatic function for the glycolytic metabolite lactate. Lactate directly suppresses signalling pathways and modifies histones to play an important role in regulating macrophage polarization, tumour immunity and antiviral responses.
Hypoxia- and glycolysis-induced lactate and acidosis suppress inflammatory macrophage activation and promote homeostatic polarization by several mechanisms at several subcellular locations.
Lactate directly modifies histones and promotes transcription of homeostatic genes.
Immunosuppressive effects of efferocytosis are mediated by lactate-induced expression of anti-inflammatory genes.
Lactate directly targets mitochondrial antiviral-signalling protein (MAVS), thus promoting homeostatic macrophage polarization indirectly by suppressing pro-inflammatory interferon-mediated pathways.
Lactate is an important regulator of tumour immunity and antiviral responses.
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O’Neill, L. A., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).
Peng, M. et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484 (2016).
Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).
Liu, N. et al. Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α-mediated tumor progression. J. Clin. Invest. 129, 631–646 (2019).
Bohn, T. et al. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat. Immunol. 19, 1319–1329 (2018).
Morioka, S. et al. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. Nature 563, 714–718 (2018).
Zhang, W. et al. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell 178, 176–189 (2019).
Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019).
Batie, M. et al. Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science 363, 1222–1226 (2019).
Chakraborty, A. A. et al. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science 363, 1217–1222 (2019).
This work was supported by grants from the US National Institutes of Health.
The author declares no competing interests.
The Nobel Prize in Physiology or Medicine 2019: https://www.nobelprize.org/prizes/medicine/2019/summary/
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Ivashkiv, L.B. The hypoxia–lactate axis tempers inflammation. Nat Rev Immunol 20, 85–86 (2020). https://doi.org/10.1038/s41577-019-0259-8
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