Non-resolving neuroinflammation regulates axon regeneration in chronic spinal cord injury.

bioRxiv, 2024 · DOI: https://doi.org/10.1101/2024.04.19.590106 · Published: April 24, 2024

Simple Explanation

Chronic spinal cord injuries (SCI) are characterized by persistent inflammation, specifically the presence of microglia and macrophages. This study investigates the role of this sustained inflammation in affecting axon regeneration. The researchers used a CSF1R inhibitor (PLX-5622) to deplete macrophages/microglia in a chronic SCI model, with or without a pro-regenerative stimulus (PTEN knockout). They then observed the effects on axon growth and functional recovery. The study found that macrophage depletion altered the microenvironment and increased axon densities of specific types, but PTEN knockout did not augment axon densities further. Inflammatory repopulation seemed to augment axon densities and also improve motor recovery.

Study Duration

13 weeks

Participants

108 mice (87 for data collection) C57BL/6J and PTEN-Flox

Evidence Level

Not specified

Key Findings

1
Macrophages and microglia repopulate the chronically injured spinal cord after depletion with PLX-5622, returning to pre-depleted levels, suggesting a homeostatic mechanism.
2
CSF1R antagonism in chronic SCI augments the growth of specific axon types (5-HT+ and CGRP+) into the lesion, independently of PTEN-KO.
3
PTEN-KO did not significantly augment axon densities within the lesion beyond effects induced by PLX-5622, suggesting that the observed axon growth was primarily of fiber types not readily transduced by AAVrg’s.

Research Summary

This study investigates the role of sustained neuroinflammation in chronic spinal cord injury (SCI) and its impact on axon regeneration. The researchers used PLX-5622 to deplete macrophages/microglia and combined it with PTEN knockout (PTEN-KO) to stimulate axon growth. The findings reveal that macrophage depletion and repopulation significantly influence the chronic SCI environment, particularly affecting the expression of neuron-enriched, secreted, and extracellular matrix-related transcripts. PLX-5622 treatment increased axon densities within the lesion, primarily of 5-HT+ and CGRP+ fibers. While PTEN-KO alone improves locomotor function, inflammatory repopulation augments this effect that was significantly different between vehicle-treated controls implicating inflammation is a regulator of axon growth and regeneration.

Practical Implications

Therapeutic Targeting of Inflammation

Modulating inflammation in chronic SCI could enhance axon regeneration of certain fiber types.

Homeostatic Mechanisms

Understanding the mechanisms that maintain elevated macrophage/microglia densities in chronic SCI may provide new therapeutic targets.

Combination Therapies

Combining anti-inflammatory strategies with pro-regenerative approaches may improve functional outcomes after SCI.

Study Limitations

1
The study focused on a complete spinal crush injury model, which may not fully represent the heterogeneity of human SCI.
2
AAVrg's limitations in transducing certain axon subtypes (5-HT+ and CGRP+).
3
The focus on intralesional axon growth did not address potential regenerative responses through spared tissue or astroglial bridges.

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