Stimulation of Monocytes, Macrophages, and Microglia by Amphotericin B and Macrophage Colony-Stimulating Factor Promotes Remyelination

The Journal of Neuroscience, 2015 · DOI: 10.1523/JNEUROSCI.1797-14.2015 · Published: January 21, 2015

Simple Explanation

The study investigates ways to encourage myelin repair after demyelination. Activating immune cells with existing medications could help, as a controlled inflammatory response can stimulate growth factors and remove debris. Amphotericin B, an antifungal drug, can activate monocytes, macrophages, and microglia. When mice with spinal cord demyelination were treated with amphotericin B and macrophage colony-stimulating factor (MCSF), more microglia/macrophages appeared at the injury site. This treatment, especially with both drugs, boosted oligodendrocyte precursor cells and remyelination. Reducing monocytes and macrophages with clodronate liposomes weakened these regenerative effects. The findings suggest that existing medications could potentially be used to help repair myelin.

Study Duration

Not specified

Participants

C57BL/6 female mice between 8 and 10 weeks of age

Evidence Level

Not specified

Key Findings

1
Amphotericin B (AmpB) activates monocytes, macrophages, and microglia through MyD88/TRIF signaling.
2
Systemic injections of AmpB and macrophage colony-stimulating factor (MCSF) increased the representation of microglia/macrophages at the site of lysolecithin-induced demyelination in the spinal cord of mice.
3
Treatment with AmpB, particularly in combination with MCSF, increased the number of oligodendrocyte precursor cells and promoted remyelination within lesions; these pro-regenerative effects were mitigated in mice treated with clodronate liposomes.

Research Summary

This study investigates the potential of using clinically approved medications to stimulate remyelination by activating monocytes, macrophages, and microglia. Amphotericin B (AmpB) was identified as an activator of these cells and its effects, alone and in combination with macrophage colony-stimulating factor (MCSF), were examined in a lysolecithin-induced demyelination model in mice. The study found that AmpB activates macrophages and microglia through toll-like receptor signaling, specifically requiring the MyD88/TRIF pathway. The combination of AmpB and MCSF further promoted the accumulation and activity of microglia/macrophages at the lesion site and enhanced the expression of scavenger receptors. Importantly, treatment with AmpB and MCSF increased the number of oligodendrocyte precursor cells and promoted remyelination, while depletion of monocytes and macrophages with clodronate liposomes reversed the therapeutic effects of AmpB/MCSF. These findings suggest that judicious use of medications to promote the activity of monocytes, macrophages, and microglia could be a potential therapy for myelin repair.

Practical Implications

Potential therapeutic strategy for demyelinating diseases

The study identifies a potential therapeutic strategy for promoting remyelination in demyelinating diseases such as multiple sclerosis (MS) and spinal cord injury by stimulating the activity of monocytes, macrophages, and microglia with FDA-approved medications.

Clinical translation of Amphotericin B

As Amphotericin B is already available for human use, albeit with significant toxicity, its translation as a therapeutic agent to stimulate remyelination may be expedited, particularly with the development of less toxic formulations and delivery methods.

Combination therapy for enhanced remyelination

The study suggests that a combination therapy using Amphotericin B and MCSF can enhance remyelination, providing a rationale for exploring combination approaches to maximize therapeutic efficacy.

Study Limitations

1
The study uses a lysolecithin-induced demyelination model, which may not fully represent the complexity of chronic demyelinating diseases such as multiple sclerosis.
2
The potential toxicity of Amphotericin B at higher doses needs to be carefully considered when translating these findings to human clinical trials.
3
The study does not fully elucidate the specific mechanisms by which monocytes, macrophages, and microglia promote remyelination in response to Amphotericin B and MCSF.

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