Complementing Neuroregeneration: Deciphering the Role of Neuro-Immune Interactions in CNS Repair

The review discusses how inflammation, once thought to only harm the CNS, actually has neuroregenerative potential. The inflammatory response can be both pro- and anti-inflammatory, and both contribute to repair. Understanding inflammatory factors after nerve injury is important to distinguish factors that worsen damage from factors that support regeneration. The complement cascade is involved in clearing pathogens, modulating lymphocytes, and attracting/activating myeloid cells. The proteins C1q and C3, and the receptor CR3 are involved in pathways where C1q initiates the cleavage of C3 which acts on CR3 to stimulate phagocytosis. Peterson et al. (2021) characterized the roles of C3, C1q, and CR3 during axon regeneration in a model of optic nerve injury in mice. They found that complement factors are required for regeneration, and that CR3-expressing myeloid cells bolster myelin debris clearance to enhance axon growth.

• 1
  C3 expression rapidly increased in the optic nerve after crush injury, followed by a steady increase in C1q expression. CR3+ cells increased from 1 day post-injury up to 14 days.
• 2
  C1q, C3, or CR3 knockout mice exhibited significantly less axon regeneration than wild-type mice in response to pro-regenerative treatments, suggesting that complement factors are required for regeneration.
• 3
  MBP from damaged myelinated axons was greatly attenuated in regions with phagocytic CR3+/CD68+ microglia/macrophages. GAP43+ axonal regrowth occurred almost exclusively in CR3+/CD68+ regions devoid of MBP.