Zinc Promotes Microglial Autophagy Through NLRP3 Inflammasome Inactivation via XIST/miR-374a-5p Axis in Spinal Cord Injury.

Abstract

Zinc has reported to play a neuroprotective role in the development of spinal cord injury (SCI). The protective mechanism of zinc remains to be uncovered. The aim of the current study was to investigate the neuroprotective mechanism of zinc in the progression of SCI. The C57BL/6J mouse SCI model was established to confirm the protective role of zinc in vivo, while the cellular model was induced in mouse microglial BV2 cells by using lipopolysaccharide (LPS). The expression levels of XIST, miR-374a-5p and NLRP3 inflammasome as well as the autophagy-related proteins were detected using real-time PCR and immunoblotting. Cell viability was assessed by CCK-8 assay. Apoptosis was evaluated by TUNEL staining, flow cytometry, the determination of apoptosis-related proteins. The target relationship was confirmed by luciferase reporter assays. Zinc improved locomotor function in SCI mice and alleviated LPS-induced BV2 cell injuries by inhibiting apoptosis and initiating autophagy processes. XIST and NLRP3 inflammasome was upregulated while miR-374a-5p was downregulated in spinal cords of SCI mice and LPS-treated BV2 cells. All these effects were inhibited by Zinc treatment. XIST knockdown triggered microglial autophagy-mediated NLRP3 inactivation in LPS-induced BV2 cells by regulating miR-374a-5p. Zinc treatment protected BV2 cells from LPS-induced cell injury by the downregulation of XIST. This process might be through autophagy‑mediated NLRP3 inflammasome inactivation by targeting miR-374a-5p. Zinc downregulates XIST and induces neuroprotective effects against SCI by promoting microglial autophagy-induced NLRP3 inflammasome inactivation through regulating miR-374a-5p. Our finding provides novel opportunities for the understanding of zinc-related therapy of SCI.

• Authors: Xiaoguang Zhao, Jufeng Sun, Yajiang Yuan, Sen Lin, Jiaquan Lin, Xifan Mei
• Journal: Neurochemical research (Neurochem Res) Vol. 47 Issue 2 Pg. 372-381 (Feb 2022) ISSN: 1573-6903 [Electronic] United States
• PMID: 34585283 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Inflammasomes
• MicroRNAs
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Zinc

Topics

• Animals
• Autophagy
• Inflammasomes (metabolism)
• Mice
• Mice, Inbred C57BL
• MicroRNAs (metabolism)
• Microglia (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Spinal Cord Injuries (drug therapy, metabolism)
• Zinc (metabolism)