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Exosomal Circ_STAT1-AS Delivery Induced by Dexmedetomidine Modulates Microglial Polarization to Alleviate Diabetic
Yu Wei1,2, Xiaoling Zeng1,2, Fujun Li3
1Department of Anesthesia, Liuzhou Worker's Hospital/The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, China.
Backgruound:
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus, characterized by neuroinflammation. Previous studies have shown that dorsal root ganglion (DRG) neurons can regulate microglial polarization. This study aims to investigate how exosomal circ_signal transducer and activator of transcription 1 (STAT1)-AS from dexmedetomidine (DEX)-treated DRG neurons affects microglial polarization in DPN.
Methods:
Exosomes were isolated from DRG neurons and identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. DPN rat model was established by high sugar and fat diet combined with streptozotocin injection. The sciatic nerve conduction velocity, mechanical withdrawal threshold, and thermal withdrawal latency of rats were measured. Hematoxylin & eosin staining and immunohistochemical staining of S100B were used to detect spinal cord tissue injury. Chromatin immunoprecipitation quantitative polymerase chain reaction detected the interaction between histone deacetylase 5 (HDAC5) and unc-13 homolog D (UNC13D) promoter, as well as the H3 acetylation at lysine 27 (H3K27) acetylation level in UNC13D promoter region.
Results:
Exosomal circ_STAT1-AS secretion from DRG neurons was enhanced by DEX treatment. These exosomes inhibited microglial M1 polarization and facilitated its M2 polarization by suppressing STAT1 translation. Mechanistically, the enhanced exosome secretion was attributed to the increased UNC13D expression, which resulted from HDAC5 inhibition and subsequent elevation of H3K27 acetylation modification at UNC13D promoter under DEX treatment. In DPN rat model, intrathecal administration of circ_STAT1-AS-enriched exosomes alleviated neuropathic symptoms and reduced neuroinflammation.
Conclusion:
Exosomal circ_STAT1-AS delivery from DRG neurons was enhanced through DEX-mediated HDAC5/UNC13D axis. The increased exosomal circ_STAT1-AS absorbed by microglia suppressed STAT1 translation to inactivate JAK/STAT1 pathway, thereby modulating microglial M1/M2 polarization balance and alleviating DPN.
