Activated microglia inhibit axonal growth through RGMa

Area of Science:

• Neuroscience
• Immunology
• Regenerative Medicine

Background:

• Spinal cord injuries (SCI) cause significant motor and sensory deficits due to limited neural regeneration in the adult central nervous system (CNS).
• Activated microglia accumulate at SCI lesions and can influence pathophysiological outcomes.
• Microglia are implicated in the inhibition of axonal growth following CNS injury.

Purpose of the Study:

• To investigate the role of activated microglia in inhibiting axonal growth after SCI.
• To identify the specific molecular mechanisms by which microglia impede neural regeneration.
• To evaluate the therapeutic potential of inhibiting microglial activation for promoting recovery after SCI.

Main Methods:

• In vitro studies using primary cortical neurons and lipopolysaccharide (LPS)-activated microglia to assess neurite outgrowth and growth cone collapse.
• Utilized RGMa-neutralizing antibodies and RGMa siRNA to block RGMa function.
• Administered minocycline, a microglial activation inhibitor, in an in vivo mouse SCI model.
• Assessed microglial accumulation, RGMa expression, and corticospinal tract dieback post-SCI.

Main Results:

• LPS-activated microglia directly inhibited neuronal neurite outgrowth and induced growth cone collapse in vitro.
• Microglia increased RGMa expression upon LPS activation, mediating the inhibitory effect on axonal growth.
• RGMa neutralization or knockdown attenuated microglial-induced axonal growth inhibition.
• Minocycline treatment reduced microglial activation and RGMa expression in vivo, decreasing axonal dieback after SCI.

Conclusions:

• Activated microglia inhibit axonal regeneration in the injured CNS primarily through the repulsive guidance molecule a (RGMa).
• Targeting microglial activation, for example, with minocycline, represents a promising therapeutic strategy to enhance axonal regrowth and functional recovery after spinal cord injury.