Modulating Microglial Activation to Elicit Axonal Regeneration

Spinal cord injury (SCI) frequently results in severe and permanent neurological deficits. Adult central nervous system neurons exhibit limited spontaneous regeneration due to intrinsic constraints and the inhibitory post-injury environment. We observed an early activation of CCL2, peaking at 30% upregulation six hours post-SCI at the lesion site, compared to later time points. While CCL2/MCP1 is known to recruit macrophages, exacerbating inflammation at the lesion site, we also detected its upregulation in the brain three days post-injury. This correlated with a twofold reduction in synaptic density within the primary motor cortex, accompanied by morphological changes in cortical microglia. Furthermore, transferring cerebrospinal fluid (CSF) from SCI animals to healthy animals resulted in a significant reduction in axonal growth in cultured neurons exposed to the recipient CSF seven days post-lesion (p<0.02). These findings suggest that the integrity of corticospinal tract (CST) neurons in the motor cortex is critical for regenerative capacity. We hypothesize that peripheral neutralization of CCL2 will mitigate both local lesion inflammation and the detrimental cortical effects, fostering a more conducive environment for axonal regeneration. The present study investigates the effects of neutralizing CCL2 with an antibody, administered immediately following SCI, compared to an isotype control. In animals treated with CCL2 antibody or isotype, we assess the regenerative potential of host cortical neurons within a stem cell-enriched lesion cavity. This research addresses corticospinal regeneration in SCI, aiming that modulating cortical microglial reactivity can be a strategy to overcome the regenerative limitations of CST neurons, potentially improving patient outcomes.

Recommended citation: Ramos Cavalcanti, R., Nguyen, K., Chang, E., Almeida, F., Blanco Martinez, A. M., & Marques de Freria, C. (2025). Modulating microglial activation to elicit axonal regeneration [Abstract DB16]. Journal of Neurotrauma, 42(13–14), e1109–e1229. https://doi.org/10.1089/neu.2025.86661.abstract