The hypoxia-lactate axis tempers inflammation

Abstract

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.

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

Multiple disease states such as tumours, chronic inflammation and tissue injury are characterized by increased glycolysis, acidosis and lactate concentrations. Lactate molecules are imported into infiltrating macrophages, which also produce increased amounts of lactate in response to hypoxia and inflammatory activation (for example, by TLR ligands). Lactate and related acidosis suppress inflammatory macrophage activation and promote homeostatic M2-like polarization by several mechanisms. a | Acidosis signals via plasma membrane GPCRs to activate cAMP signalling and induce CREM expression. b | Lactate acts at lysosomes to activate mTORC1 and HIF2α. c | Lactate acts at mitochondria by binding to MAVS and inhibiting its interaction with RIG-I. d | Lactate acts in the nucleus via histone lactylation, which promotes transcription of homeostatic genes. e | In addition to inducing histone lactylation, hypoxia directly activates histone demethylases KDM6A and KDM5A, which remodel chromatin in conjunction with histone lactylation.