The hypoxia-lactate axis tempers inflammation

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. 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. Studies in the field of inflammation in 2019 have highlighted a counterbalancing homeostatic function for the glycolytic metabolite lactate, which is produced in hypoxic conditions, such as in tumours and chronic inflammation. Lionel Ivashkiv describes how lactate suppresses inflammatory signalling pathways and regulates macrophage polarization.