Unravelling the role of microglial MCT4 in ischemic stroke

Microglia are crucial players in brain injury, orchestrating inflammatory responses, scavenging cellular debris, and promoting plasticity for functional recovery. To perform these functions, microglia undergo specific metabolic adaptations. Ex vivo evidence shows that, when subjected to glucose depletion, microglia are able to maintain their motility and surveillance, thanks to their high metabolic flexibility. However, the energetic sources sustaining their flexibility in vivo remain unclear. Ischemic stroke is characterized by a sudden drop in nutrients and oxygen supply, while extracellular lactate levels rise after ischemia. Interestingly, lactate administration in preclinical models correlates with positive outcomes, pointing to lactate as a central metabolite in this context. We previously found that microglia exposed to lactate upregulate the monocarboxylate transporter MCT4, promoting their lysosomal acidification. Here, we hypothesize that following ischemic stroke microglia can enhance lactate utilization, coupling this metabolic adaptation with increased phagocytic capacity and improved tissue repair. To this aim, we used a microglial-specific MCT4 conditional KO (MCT4 cKO) mouse line and performed transient middle cerebral artery occlusion (tMCAO). Preliminary data indicate that the levels of IBA1+ microglia and CD68+ phagolysosomes are reduced in the infarct area of cKO mice, along with diminished number of microglia-neuron contacts. Neurological examinations also support a delayed recovery in cKO mice. Altogether, our data suggest that MCT4 is implicated in the microglial response to ischemia. Further research is needed to fully elucidate the mechanisms underlying microglial MCT4 function and to explore its potential as a therapeutic target for the management of ischemic stroke.