Dynamic Modulation of Microglia/Macrophage Polarization by miR-124 after Focal Cerebral Ischemia

Abstract

Mononuclear phagocytes respond to ischemic stroke dynamically, undergoing an early anti-inflammatory and protective phenotype followed by the pro-inflammatory and detrimental type. These dual roles of microglia/macrophages suggest the need of subtle adjustment of their polarization state instead of broad suppression. The most abundant brain-specific miRNA, miR-124, promotes neuronal differentiation but can also modulate microglia activation and keeps them in a quiescent state. We addressed whether the intracerebral injection of miR-124 in a mouse model of ischemic stroke before or after the peak phase of the pro-inflammatory polarization modifies the pro−/anti- inflammatory balance. In the sub-acute phase, 48 h after stroke, liposomated miR-124 shifted the predominantly pro-inflammatory polarized microglia/macrophages toward the anti-inflammatory phenotype. The altered immune response improved neurological deficit at day 6 after stroke. When miR-124 was injected 10 days after stroke, the pro−/anti- inflammatory ratio was still significantly reduced although to a lower degree and had no effect on recovery at day 14. This study indicates that miR-124 administration before the peak of the pro-inflammatory process of stroke is most effective in support of increasing the rehabilitation opportunity in the sub-acute phases of stroke. Our findings highlight the important role of immune cells after stroke and the therapeutic relevance of their polarization balance.