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INFLAMMATION IN 2019

The hypoxia–lactate axis tempers inflammation

Nature Reviews Immunology volume 20, pages 85–86 (2020)Cite this article

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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.

Key advances

  • 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.

The Nobel Prize in Physiology or Medicine 2019 celebrated the discovery of the molecular mechanisms by which cells sense and respond to low oxygen levels (known as hypoxia). A key mediator of hypoxic responses is the transcription factor hypoxia-inducible factor 1α (HIF1α), which is stabilized under low oxygen conditions and translocates to the nucleus to bind to hypoxia-regulated genes. These genes promote cellular metabolic adaptation, in particular anaerobic glycolysis, and encode proteins such as vascular endothelial growth factor (VEGF) and erythropoietin that are important for the generation of new blood vessels and red blood cells. Hypoxia occurs in many disease states including tumours, infections, ischaemia and inflammation.

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Fig. 1: Central role for lactate in promoting macrophage polarization under conditions of hypoxia.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health.

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Authors and Affiliations

  1. Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA

    Lionel B. Ivashkiv

  2. Department of Medicine and Program in Immunology and Microbial Pathogenesis, Weill Cornell Medicine, New York, NY, USA

    Lionel B. Ivashkiv

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  1. Lionel B. Ivashkiv
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Correspondence to Lionel B. Ivashkiv.

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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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  • DOI: https://doi.org/10.1038/s41577-019-0259-8

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