Decreased Astrocytic CCL5 by MiR-324-5p Ameliorates Ischemic Stroke Injury via CCR5/ERK/CREB Pathway

Abstract

AbstractFollowing ischemic stroke, Ccl5 mRNA expression increased, while miR-324-5p expression decreased in the peri-infract cortex of middle cerebral artery occlusion (MCAO) mice. However, the roles of CCL5 and miR-324-5p in stroke remain unclear. Here, we show that inhibiting CCL5 using antibodies or miR-324-5p not only reduced infarct area and preserved neurological function in MCAO mice but also attenuated astrocyte and microglia activation, protected dendritic structures, and maintained spine density. In an astrocyte-neuron co-culture system after oxygen-glucose deprivation (OGD), knockdown astrocytic CCL5 expression by antibody or miR-324-5p decreased neuronal apoptosis and preserved dendritic architecture. Importantly, the suppression of CCL5 enhanced the activation of the ERK/CREB pathway both in vivo and in vitro. Consistent with these findings, the application of Maraviroc, a CCR5 antagonist, reduced infarct size, decreased neuronal apoptosis, and upregulated the ERK/CREB pathway in neurons treated with OGD. In conclusion, targeting the CCL5 pathway via miR-324-5p represents a promising therapeutic strategy for alleviating ischemic stroke damage through modulation of neuronal CCR5/ERK/CREB pathway.