Extracellular lactate enhances IL-10 transcription via H4K5 lactylation and promotes an A2-like reactive-astrocyte phenotype after ischemic stroke.
Abstract
Background
Ischemic stroke triggers a rapid rise in lactate levels in the brain tissue. The neuroprotective role of exogenous lactate administered during the reperfusion phase has recently garnered attention. A neuroprotective A2 phenotype of reactive astrocytes (RACs) is characterized by interleukin-10 (IL-10) upregulation, which mitigates neuroinflammation. However, whether exogenous lactate drives A2-like polarization of RACs remains unknown. This study aimed to elucidate the mechanism by which lactate regulates this process.
Methods
Rat middle cerebral artery occlusion (MCAO) and in vitro primary RACs models were established. Western blotting, immunofluorescence staining, and RT-qPCR were used to assess A1/A2 polarization markers, IL-10 expression, histone lactylation, and related neuroimmune signaling molecules. Ubiquitination, chromatin immunoprecipitation, and dual-luciferase reporter assays were performed to clarify the mechanism by which lactate regulates IL-10 expression and A2-like polarization of RACs.
Results
Our results demonstrated that increased lactate levels after ischemic stroke correlated with A2 polarization of RACs. Lactate treatment significantly enhanced A2 polarization and reduced infarct volume in the rat MCAO model. Mechanistically, lactate activated signal transducer and activator of transcription 3 (STAT3) signaling while suppressing sirtuin 1 (SIRT1) expression and synergistically enhancing H4K5 lactylation (H4K5la) and IL-10 expression, thereby driving RACs toward an anti-inflammatory phenotype.
Conclusions
This study revealed that elevated extracellular lactate in the acute phase of ischemic stroke drove RACs toward an A2-like phenotype through the Yes-associated protein 1 (YAP1)/STAT3/IL-10 and YAP1/SIRT1/H4K5la signaling axes. These findings provide a theoretical basis for targeting RAC lactylation as a potential therapeutic strategy to limit inflammatory damage after stroke.