Neuronal extracellular vesicle derived miR-98 prevents salvageable neurons from microglial phagocytosis in acute ischemic stroke

Abstract

Extracellular vesicles (EVs), as a novel intercellular communication carrier transferring cargo microRNAs (miRNAs), could play important roles in the brain remodeling process after ischemic stroke. However, the detailed mechanisms involved in EVs derived miRNAs-mediated cellular interactions in the brain remain unclear. Several studies indicated that microRNA-98 (miR-98) might participate in the pathogenesis of ischemic stroke. Here, we showed that expression of miR-98 in penumbra field kept up on the first day but dropped sharply on the 3rd day after ischemic stroke in rats, indicating that miR-98 could function as an endogenous protective factor post-ischemia. Overexpression of miR-98 targeted inhibiting platelet activating factor receptor-mediated microglial phagocytosis to attenuate neuronal death. Furthermore, we showed that neurons transferred miR-98 to microglia via EVs secretion after ischemic stroke, to prevent the stress-but-viable neurons from microglial phagocytosis. Therefore, we reveal that EVs derived miR-98 act as an intercellular signal mediating neurons and microglia communication during the brain remodeling after ischemic stroke. The present work provides a novel insight into the roles of EVs in the stroke pathogenesis and a new EVs-miRNAs-based therapeutic strategy for stroke.

BK Channel-Mediated Microglial Phagocytosis Alleviates Neurological Deficit After Ischemic Stroke

“…Four-week minocycline treatment at 4 days after tMCAO decreased the number of activated microglia and increased the number of BrdU + /NeuN + cells ( Liu et al, 2007 ). Overexpressing miR-98 inhibited microglial phagocytosis to attenuate neuronal death in the penumbra area at 3 days after tMCAO ( Yang et al, 2021 ). However, microglial phagocytotic receptor TREM2 knockout mice showed less tissue resorption and a larger lesion area, along with severe limb bias, which suggested that microglial phagocytosis improved synapse and axon regeneration after injury ( Werneburg et al, 2020 ).…”

Dysfunction of the Neurovascular Unit in Ischemic Stroke: Highlights on microRNAs and Exosomes as Potential Biomarkers and Therapy

“…This effect was attributed to chemokine CXC motif ligand 1 (CXCL1), a target gene of miR-181-3p, which was downregulated by this miR in astrocytes [ 40 ]. Furthermore, miR-98 derived from Ne-Exos acts as a post-ischemic endogenous protective factor by inhibiting microglial phagocytosis via the targeting of platelet-activating factor receptor (PAFR), thereby attenuating ischemia-induced neuronal death [ 41 ]. In addition, Xu et al revealed that neurons transfer miR-132 to endothelial cells via secreting exosomes.…”

Efferocytosis Mediated Modulation of Injury after Neonatal Brain Hypoxia-Ischemia

“…The undesired effects of excessive efferocytosis of distressed yet viable neurons can be prevented by therapies focused on administration of extracellular vesicles containing molecules such as miR-98. In a model of ischemic stroke, miR-98-loaded extracellular vesicles prevented the stressed but viable neurons from microglial phagocytosis [ 143 ]. The miR-98 acts via the platelet activating factor receptor (PAFR) that mediates efferocytosis as observed during engulfment of excitatory synapses of hippocampus in a model of experimental auto-immune encephalomyelitis [ 144 ] or apoptotic thymocytes in cell culture [ 145 ].…”