Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Year in Review
  • Published:

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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

References

  1. O’Neill, L. A., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).

    Article  Google Scholar 

  2. Peng, M. et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484 (2016).

    Article  CAS  Google Scholar 

  3. Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).

    Article  CAS  Google Scholar 

  4. 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).

    Article  Google Scholar 

  5. Bohn, T. et al. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat. Immunol. 19, 1319–1329 (2018).

    Article  CAS  Google Scholar 

  6. Morioka, S. et al. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. Nature 563, 714–718 (2018).

    Article  CAS  Google Scholar 

  7. Zhang, W. et al. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell 178, 176–189 (2019).

    Article  CAS  Google Scholar 

  8. Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019).

    Article  CAS  Google Scholar 

  9. Batie, M. et al. Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science 363, 1222–1226 (2019).

    Article  CAS  Google Scholar 

  10. Chakraborty, A. A. et al. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science 363, 1217–1222 (2019).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lionel B. Ivashkiv.

Ethics declarations

Competing interests

The author declares no competing interests.

Additional information

Related links

The Nobel Prize in Physiology or Medicine 2019: https://www.nobelprize.org/prizes/medicine/2019/summary/

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

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

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing