Harnessing the Benefits of Neuroinflammation: Generation of Macrophages/Microglia with Prominent Remyelinating Properties

The Journal of Neuroscience, 2021 · DOI: https://doi.org/10.1523/JNEUROSCI.1948-20.2021 · Published: April 14, 2021

Immunology Regenerative Medicine & Stem Cells

Simple Explanation

Inflammation in the brain and spinal cord can be harmful, but it can also help with repair. This study found that a specific combination of signals can create a type of immune cell that is particularly good at repairing damage to the protective coating around nerve fibers (myelin). The researchers discovered that exposing immune cells called macrophages and microglia to a mix of LPS (a pro-inflammatory signal) and IL4/IL13 (regulatory signals) created a unique type of cell. These cells had properties that promoted myelin repair without causing harmful inflammation. When this combination was applied to spinal cord injuries in mice, it led to increased myelin production and repair. This suggests that carefully using this mixture could help the nervous system recover from injury.

Study Duration

Not specified

Participants

C57BL/6 female mice

Evidence Level

Not specified

Key Findings

1
The combination of LPS and regulatory IL4 and IL13 signaling in macrophages and microglia produces a reparative phenotype devoid of pro-inflammatory neurotoxic features.
2
Local administration of LPS/IL4/IL13 into spinal cord lesions elicits profound oligodendrogenesis and remyelination.
3
The M(LPS/IL4/IL13) macrophages had a prominent rise of the IL10 regulatory cytokine and CCL2 chemokine, while IL12 was not detected despite the use of LPS

Research Summary

The study investigates how to harness the beneficial aspects of neuroinflammation to promote regeneration, focusing on macrophages and microglia. It reveals that the combination of LPS (a pro-inflammatory stimulus) with IL4 and IL13 (regulatory cytokines) generates a unique macrophage/microglia phenotype (M(LPS/IL4/IL13)) with enhanced reparative properties and reduced neurotoxicity. In a mouse model of spinal cord demyelination, local application of LPS/IL4/IL13 promoted oligodendrogenesis and remyelination, suggesting a potential translational application for enhancing neural repair in CNS injuries.

Practical Implications

Therapeutic Potential

The LPS/IL4/IL13 mixture could be locally applied to focal CNS injuries to enhance neural regeneration and recovery.

Targeted Neuroinflammation

Careful use of the LPS and IL4/IL13 mixture could harness the known benefits of neuroinflammation to enable repair in neurologic insults.

Drug Development

Identify therapeutics that stimulate the downstream pathways unleashed by the LPS/IL4/IL13, so as to produce these remarkable macrophages that can be helpful in a variety of neurologic and non-neurologic conditions.

Study Limitations

1
The activators would not be conducive for systemic application
2
Inability to discriminate monocyte-derived macrophages from microglia
3
The phenomenon of LPS preconditioning, whereby a prior exposure to LPS leads to reduced pathophysiology on a subsequent insult, has been described for some time

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