Dorsal root ganglion-derived exosomes deteriorate neuropathic pain by activating microglia via the microRNA-16-5p/HECTD1/HSP90 axis

• Published in: Biological research Vol. 57; no. 1; pp. 28 - 15
• Main Authors: Xing, Yinghao, Li, Pei, Jia, Yuanyuan, Zhang, Kexin, Liu, Ming, Jiang, Jingjing
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 15.05.2024; BioMed Central; Sociedad de Biología de Chile; BMC
• Subjects: Analysis; Animals; Binding sites; BIOLOGY; Biotechnology industry; Cells; Cold; Disease Models, Animal; Dorsal root ganglia; Dorsal root ganglion-derived exosomes; Exosomes; Exosomes - metabolism; Fluorescent antibody technique; Ganglia, Spinal - metabolism; Ganglion; Heat shock proteins; HECTD1; HSP90; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Hyperalgesia; Immunofluorescence; Inflammation; Male; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; MicroRNA; microRNA-16-5p; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Nervous system; Neuralgia; Neuralgia - genetics; Neuralgia - metabolism; Neuropathic pain; Pain; Scientific equipment and supplies industry; Spinal cord; Spinal nerves; Ubiquitin; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; United States; China; HSP90; HECTD1; microRNA-16-5p; Dorsal root ganglion-derived exosomes; Neuropathic pain
• ISSN: 0717-6287; 0716-9760; 0717-6287
• DOI: 10.1186/s40659-024-00513-1

The activated microglia have been reported as pillar factors in neuropathic pain (NP) pathology, but the molecules driving pain-inducible microglial activation require further exploration. In this study, we investigated the effect of dorsal root ganglion (DRG)-derived exosomes (Exo) on microglial activation and the related mechanism. A mouse model of NP was generated by spinal nerve ligation (SNL), and DRG-derived Exo were extracted. The effects of DRG-Exo on NP and microglial activation in SNL mice were evaluated using behavioral tests, HE staining, immunofluorescence, and western blot. Next, the differentially enriched microRNAs (miRNAs) in DRG-Exo-treated microglia were analyzed using microarrays. RT-qPCR, RNA pull-down, dual-luciferase reporter assay, and immunofluorescence were conducted to verify the binding relation between miR-16-5p and HECTD1. Finally, the effects of ubiquitination modification of HSP90 by HECTD1 on NP progression and microglial activation were investigated by Co-IP, western blot, immunofluorescence assays, and rescue experiments. DRG-Exo aggravated NP resulting from SNL in mice, promoted the activation of microglia in DRG, and increased neuroinflammation. miR-16-5p knockdown in DRG-Exo alleviated the stimulating effects of DRG-Exo on NP and microglial activation. DRG-Exo regulated the ubiquitination of HSP90 through the interaction between miR-16-5p and HECTD1. Ubiquitination alteration of HSP90 was involved in microglial activation during NP. miR-16-5p shuttled by DRG-Exo regulated the ubiquitination of HSP90 by interacting with HECTD1, thereby contributing to the microglial activation in NP.