Microglial IKKβ Alters Central and Peripheral Immune Activity at Distinct Time Points After Spinal Cord Injury

Area of Science:

• Neuroscience
• Immunology
• Molecular Biology

Background:

• Persistent microglial activation after spinal cord injury (SCI) drives neuroplasticity and contributes to sympathetic dysfunction and immune disorders.
• Nuclear factor-kappa B (NF-κB) signaling is activated post-SCI, creating a pro-inflammatory feedback loop involving inflammatory mediators.
• The spinal sympathetic reflex (SSR) circuit in the thoracolumbar cord is implicated in SCI-related sympathetic dysfunction.

Purpose of the Study:

• To investigate the role of microglial NF-κB signaling, specifically via the IKKβ activator, in modulating microglial activity and neuroimmune responses post-SCI.
• To determine the impact of deleting microglial IKKβ on central and peripheral immune activity related to the SSR circuit.

Main Methods:

• Utilized a mouse model with targeted deletion of IKKβ in CNS-resident microglia.
• Assessed microglial activation, polarization (M1/M2), and central transcriptional activity at 1 and 4 weeks post-SCI (wpi).
• Evaluated peripheral immune activity, including splenocyte quantity, post-SCI.

Main Results:

• Transcriptomic analysis revealed microglial IKKβ influences immune-related pathways in the thoracolumbar cord at 1 wpi.
• Deletion of microglial IKKβ mitigated the SCI-induced increase in pro-inflammatory M1 microglia in the thoracolumbar cord at 4 wpi.
• Inhibition of microglial NF-κB signaling via IKKβ deletion led to an increased quantity of splenocytes at 1 wpi.

Conclusions:

• Microglial IKKβ signaling is a key regulator of the neuroimmune response following SCI.
• Targeting microglial NF-κB signaling pathways, such as through IKKβ inhibition, may offer therapeutic strategies for managing SCI-induced immune dysregulation.
• This research enhances understanding of how microglial signaling impacts both the central nervous system and peripheral immune organs after SCI.