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Published on: January 30, 2014
Immunoproteasome subunit PSMB8 regulates microglia-mediated neuroinflammation upon manganese exposure by PERK
Tingting Guo1, Chunyan Liu2, Changhao Yang3
1Medical School of Chinese PLA: Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, China; Department of Neurology, The Second Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China.
Abstract:
Excessive manganese (Mn) exposure gives rise to various neurological disorders, including motor dysfunction and cognitive impairment. Microglia-mediated neuroinflammation plays an essential role in the pathogenesis of Mn neurotoxicity. However, the underlying mechanisms have not been fully clarified. Immunoproteasome is a specialized proteasome. Recent studies have shown that immunoproteasome, especially catalytic subunit PSMB8, is highly associated with various neurological diseases. Whether PSMB8 is involved in Mn-neurotoxicity is still unknown. In this study, in vivo and in vitro models were established, and our data showed that Mn exposure upregulated the expression and activity of PSMB8. Selective inhibition of PSMB8 mitigated neuroinflammation with reduced microglial activation and fewer TNF-α, iNOS, and CCL12 production in Mn-treated mice and BV2 cells. Learning and memory tests and Golgi staining further confirmed that inhibition of PSMB8 alleviated Mn-induced recognition memory impairments and synapse deficits. Besides, we found that blocking of PERK signaling inhibited Mn-induced elevation of PSMB8. And inhibition of PSMB8 reduced the phosphorylation of NF-κB p65. Together, our data demonstrated that PSMB8 played an essential role in microglia-mediated neuroinflammation upon Mn exposure, and the underlying mechanisms may be via PERK/NF-κB pathways. These results provide a novel target for the prevention and treatment of Mn-neurotoxicity.
Insights
Excessive manganese exposure causes neurotoxicity. This study reveals immunoproteasome subunit PSMB8 is key in manganese-induced neuroinflammation and cognitive deficits, offering a new therapeutic target.
Area of Science:
- Neuroscience
- Toxicology
- Immunology
Background:
- Manganese (Mn) neurotoxicity causes motor and cognitive impairments.
- Microglia-mediated neuroinflammation is central to Mn neurotoxicity, but mechanisms are unclear.
- Immunoproteasome subunit PSMB8 is linked to neurological diseases.
Purpose of the Study:
- To investigate the role of PSMB8 in Mn-induced neurotoxicity.
- To elucidate the underlying mechanisms of PSMB8 involvement.
- To identify potential therapeutic targets for Mn neurotoxicity.
Main Methods:
- Established in vivo (mice) and in vitro (BV2 cells) models of Mn exposure.
- Assessed PSMB8 expression, activity, and the effects of its inhibition.
- Utilized learning/memory tests, Golgi staining, and Western blotting for pathway analysis (PERK/NF-κB).
Main Results:
- Mn exposure upregulated PSMB8 expression and activity.
- Selective PSMB8 inhibition reduced microglial activation and inflammatory markers (TNF-α, iNOS, CCL12).
- PSMB8 inhibition alleviated cognitive deficits and synaptic impairments, involving PERK/NF-κB pathways.
Conclusions:
- PSMB8 plays a critical role in microglia-mediated neuroinflammation and cognitive deficits following Mn exposure.
- The PERK/NF-κB pathway mediates Mn-induced PSMB8 elevation and subsequent neuroinflammation.
- PSMB8 inhibition presents a promising therapeutic strategy for Mn neurotoxicity.
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