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INFLAMMATION IN 2019

The hypoxia–lactate axis tempers inflammation

Subjects

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.

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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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Correspondence to Lionel B. Ivashkiv.

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The author declares no competing interests.

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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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