Abstract: Spinal cord injury is a critical event characterized by intricate pathogenic mechanisms. Although recent studies have highlighted tissue exosomes as key mediators of inflammatory responses in diverse organs and tissues, their role in spinal cord injury has yet to be determined. In this study, we investigated the role and mechanisms of spinal cord tissue exosomes in the inflammatory response following spinal cord injury. We found morphological, concentration, and functional differences between exosomes extracted from injured and normal spinal cord tissues, and identified proinflammatory effects associated with spinal cord injury–generated tissue exosomes but not with exosomes derived from normal spinal cord tissue. Our in vivo and in vitro analyses showed that spinal cord injury–generated tissue exosomes promoted microglial M1 polarization and inflammatory cytokine expression, thereby exacerbating tissue and neuronal injury in the spinal cord. In addition, the combination of exosomal miRNA sequencing and experimental verification showed that the miR-155-5p level was higher in spinal cord injury–generated tissue exosomes than in spinal cord tissue. We further found that spinal cord injury–generated tissue exosomes–derived miR-155-5p induced a significant inhibition of forkhead box O3a phosphorylation and activated the nuclear factor-kappa B pathway, thereby promoting microglial M1 polarization and inflammatory cytokine expression. These findings suggest that injury-induced miR-155-5p-containing exosomes exacerbate spinal cord injury via the promotion of microglial M1 polarization and inflammatory responses. Thus, targeting miR-155-5p expression or exosome secretion could be a novel strategy for attenuating inflammation and reducing secondary injury post-spinal cord injury.

Key words: exosomes, FoxO3a, inflammatory response, microglia, miR-155-5p, neuron, nuclear factor-kappa B, spinal cord injury, spinal cord injury–generated tissue exosomes