Bone marrow mesenchymal stem cell-derived exosomal microRNA-125a promotes M2 macrophage polarization in spinal cord injury by downregulating IRF5

•B-Exo alleviates SCI symptoms in rats by promoting M2 macrophage polarization.•B-Exo treatment significantly inhibits IRF5 expression.•Overexpression of IRF5 inhibits M2 macrophage polarization caused by B-Exo.•B-Exo suppresses IRF5 expression by transferring miR-125a.•Reduction of miR-125a in B-Exo attenuates the protective effect of B-Exo on SCI rats. Spinal cord injury (SCI) may cause loss of locomotor function, and macrophage is a major cell type in response to SCI with M1- and M2-phenotypes. The protective role of bone marrow mesenchymal stem cells (BMMSC)-derived exosomes (B-Exo) in SCI has been underscored, while their regulation on M2 macrophage polarization and the mechanism remain to be clarified. A rat model of SCI was developed and treated with extracted B-Exo. Recovery of motor function was assessed by Basso-Beattie-Bresnahan (BBB) score. The apoptosis and degeneration of neurons, and macrophage polarization were evaluated. Subsequently, genes differentially expressed in the rat spinal cord after B-Exo treatment were analyzed. Later, the relationships between B-Exo and interferon regulatory factor 5 (IRF5) or macrophage polarization were clarified. Later, the upstream microRNAs (miRNAs) of IRF5 were validated by bioinformatics prediction and dual-luciferase experiments. Finally, the role of miR-125a in the neuroprotection of SCI was verified by rescue experiments. B-Exo promoted the recovery of locomotor function and M2-phenotype polarization, whereas inhibited neuronal apoptosis and degeneration and the inflammatory response caused by SCI in rats. In addition, IRF5 expression was reduced after B-Exo treatment. IRF5 promoted macrophage polarization towards M1-phenotype and secretion of inflammatory factors. There is a binding relationship between miR-125a and IRF5. Knockdown of miR-125a in B-Exo increased IRF5 expression in spinal cord tissues of SCI rats and attenuated the neuroprotective effect of B-Exo against SCI. Exosomal miR-125a derived from BMMSC exerts neuroprotective effects by targeting and negatively regulating IRF5 expression in SCI rats.