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Inhibition of 26S protease regulatory subunit 7 (MSS1) suppresses neuroinflammation
Wei Bi1, Xiuna Jing, Lihong Zhu
1Department of Neurology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
Abstract:
Recently, researchers have focused on immunosuppression induced by rifampicin. Our previous investigation found that rifampicin was neuroprotective by inhibiting the production of pro-inflammatory mediators, thereby suppressing microglial activation. In this study, using 2-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS), we discovered that 26S protease regulatory subunit 7 (MSS1) was decreased in rifampicin-treated microglia. Western blot analysis verified the downregulation of MSS1 expression by rifampicin. As it is indicated that the modulation of the ubiquitin-26S proteasome system (UPS) with proteasome inhibitors is efficacious for the treatment of neuro-inflammatory disorders, we next hypothesized that silencing MSS1 gene expression might inhibit microglial inflammation. Using RNA interference (RNAi), we showed significant reduction of IkBα degradation and NF-kB activation. The production of lipopolysaccharides-induced pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), nitric oxide, cyclooxygenase-2, and prostaglandin E(2) were also reduced by MSS1 gene knockdown. Taken together, our findings suggested that rifampicin inhibited microglial inflammation by suppressing MSS1 protein production. Silencing MSS1 gene expression decreased neuroinflammation. We concluded that MSS1 inhibition, in addition to anti-inflammatory rifampicin, might represent a novel mechanism for the treatment of neuroinflammatory disorders.
Insights
Rifampicin reduces neuroinflammation by decreasing 26S protease regulatory subunit 7 (MSS1) in microglia. Silencing MSS1 also inhibits inflammation, suggesting MSS1 inhibition as a novel therapeutic target for neuroinflammatory disorders.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Rifampicin exhibits neuroprotective effects by suppressing microglial activation and pro-inflammatory mediator production.
- The ubiquitin-26S proteasome system (UPS) is a potential target for neuro-inflammatory disorders.
Purpose of the Study:
- To investigate the role of 26S protease regulatory subunit 7 (MSS1) in rifampicin-induced immunosuppression.
- To determine if MSS1 gene silencing can inhibit microglial inflammation.
Main Methods:
- 2-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) to identify differentially expressed proteins.
- Western blot analysis to verify protein expression.
- RNA interference (RNAi) to silence MSS1 gene expression.
Main Results:
- Rifampicin treatment led to decreased MSS1 expression in microglia.
- MSS1 gene knockdown significantly reduced IkBα degradation and NF-kB activation.
- Silencing MSS1 reduced the production of pro-inflammatory mediators (iNOS, nitric oxide, COX-2, PGE2) induced by lipopolysaccharides.
Conclusions:
- Rifampicin suppresses microglial inflammation by downregulating MSS1 protein production.
- MSS1 inhibition effectively decreases neuroinflammation.
- Targeting MSS1 presents a novel therapeutic strategy for neuroinflammatory diseases.
