The E3 Ubiquitin Ligase c-Cbl Inhibits Microglia-Mediated CNS Inflammation by Regulating PI3K/Akt/NF-κB Pathway

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Background Microglia-mediated inflammation may play an important role in the pathophysiology progression of neurodegenerative diseases, such as Parkinson's disease (PD), but the molecular mechanisms are poorly understood. Aims This study sought to determine whether E3 ubiquitin ligase c-Cbl plays a role in the brain inflammation and to explore the relevant molecular mechanism. Methods After BV2 microglial cells and c-Cbl-deficient mice were treated with lipopolysaccharide (LPS), neuroinflammation and microglial activation were evaluated by immunohistochemistry, ELISA and Western blot. We further investigated the possible mechanism of c-Cbl in regulating microglial activation. Results Here, we showed that the E3 ubiquitin ligase c-Cbl had high expression in brain tissues including substantia nigra pars compacta (SNc), striatum and hippocampus, and it was abundantly expressed in microglia. Systemic LPS administration resulted in more severe microglial activation in CNS and increased expression of brain proinflammatory factors (TNF-α, IL-6, IL-1β and MCP-1) in c-Cbl knockout mice than wild type mice (WT). Downregulation of c-Cbl expression with c-Cbl siRNA in BV-2 microglial cells demonstrated a more robust increase in the proinflammatory factors release and NF-κB p65 nuclear translocation than that in control siRNA. Interestingly, Akt phosphorylation induced by LPS was also signi

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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