Intravenous administration of mesenchymal stem cell-derived exosomes mitigates traumatic brain injury by inhibiting neutrophil extracellular trap formation via miR-26a-5p.

OBJECTIVE

Traumatic brain injury (TBI) results in severe long-term sequelae. While mesenchymal stem cell-derived exosomes (MSC-Exos) have demonstrated the ability to regulate microglial responses and neuroinflammation, their impact on neutrophil inactivation, particularly in relation to neutrophil extracellular traps (NETs), has not yet been fully elucidated. This research was designed to explore the potential involvement of MSC-Exos in modulating NET formation and microglial polarization following TBI.

METHODS

A murine TBI model and an in-vitro lipopolysaccharide-induced microglial activation model were utilized to evaluate the effects of miR-26a-5p-enriched exosomes on NET inhibition, microglial polarization, reduction of neuroinflammation, and promotion of neural function recovery.

RESULTS

Treatment with MSC-Exos post-TBI reduced NET formation and decreased microglial polarization into a proinflammatory phenotype. Genome-wide prediction detected miR-26a-5p as a predominant component of MSC-Exos, which was closely associated with TAB2. Functional assays demonstrated that miR-26a-5p suppressed NET formation in neutrophils and modulated microglial polarization. MRI and histopathological assessments confirmed that MSC-Exos enriched with miR-26a-5p significantly reduced neuronal death and lesion volume. Moreover, miR-26a-5p was found to regulate microglial polarization and reduce neuroinflammation via the TAB2/JNK/AP1 signaling pathway. Cognitive assessments employing the Morris Water Maze and Modified Neurological Severity Scores revealed significant improvements in neural function following treatment.

CONCLUSION

These findings underscore the potential of MSC-Exos-miR-26a-5p to inhibit NET formation, modulate microglial polarization toward an anti-inflammatory phenotype, and enhance recovery from neural damage in TBI through the TAB2/JNK/AP1 pathway.