Activation of GLP-1R ameliorates microglial pyroptosis after spinal cord injury by restoring FANCC expression

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• Secondary spinal cord injury (SCI) involves neuroinflammation, particularly microglial pyroptosis, worsening neural damage via NLRP3 inflammasome activation.
• Liraglutide (Lr), a GLP-1 receptor (GLP-1R) agonist, shows anti-inflammatory properties, but its mechanism in SCI was unclear.

Purpose of the Study:

• To elucidate the precise mechanism by which GLP-1R activation by Lr inhibits microglial pyroptosis and promotes recovery in a murine SCI model.
• To identify key molecular mediators in the Lr-induced neuroprotective pathway.

Main Methods:

• Utilized a murine SCI model treated with high-dose Lr.
• Employed in vitro studies with RNA sequencing, pharmacological inhibition, and genetic manipulation (GLP-1R-/- mice, FANCC knockdown).
• Investigated signaling pathways including PI3K/Akt/TFEB and p38 phosphorylation.

Main Results:

• High-dose Lr improved functional and histological outcomes in SCI mice, an effect abolished in GLP-1R-/- mice.
• Lr, via the PI3K/Akt/TFEB axis, upregulated Fanconi anemia complementation group C (FANCC), suppressing pyroptosis.
• FANCC knockdown reversed Lr's anti-pyroptotic effects and increased p38 phosphorylation, confirming FANCC as a critical mediator.

Conclusions:

• A novel GLP-1R/PI3K/Akt/TFEB/FANCC/p38 pathway mediates Lr's neuroprotection in secondary SCI.
• FANCC is identified as a pivotal neuroprotective node inhibiting p38-dependent NLRP3 inflammasome activation.
• Findings support the translational potential of GLP-1R modulation for SCI treatment.