Complement C3a Suppresses Spinal Cord Neural Stem Cell Activation by Inhibiting UCHL1 via the NF-κB p65/Nrf2 Pathway

Area of Science:

• Neuroscience
• Stem Cell Biology
• Immunology

Background:

• Spinal cord injury (SCI) impairs neural stem cell (NSC) activation and neurogenesis, hindering repair.
• Reactive astrocytes release complement C3a, which was previously shown to inhibit NSC proliferation by affecting protein aggregate clearance via the UCHL1-proteasome system post-SCI.

Purpose of the Study:

• To elucidate the molecular mechanism by which C3a signaling modulates NSC activation through the UCHL1-proteasome pathway after SCI.
• To identify potential therapeutic targets for SCI repair by understanding this regulatory axis.

Main Methods:

• Investigated C3a/C3a receptor (C3aR) signaling effects on NF-κB p65 and Nrf2 activity in vitro.
• Utilized knockdown and overexpression techniques for NF-κB p65 and Nrf2.
• Performed dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) to identify UCHL1 transcriptional targets.
• Validated findings in vivo using SCI mouse models.

Main Results:

• C3a/C3aR signaling activates NF-κB p65, which suppresses Nrf2 activity and UCHL1 expression, impairing proteasome function and NSC activation.
• NF-κB p65 inhibits Nrf2 via promoting its degradation and reducing its nuclear translocation.
• UCHL1 is a direct transcriptional target of Nrf2.
• In vivo, C3aR blockade, NF-κB p65 knockdown, or Nrf2 overexpression rescued SCI-induced UCHL1 downregulation.

Conclusions:

• The C3a-NF-κB p65-Nrf2-UCHL1-proteasome axis critically regulates NSC activation following SCI.
• This pathway presents novel molecular targets for developing therapeutic strategies for spinal cord injury repair.