Azithromycin drives alternative macrophage activation and improves recovery and tissue sparing in contusion spinal cord injury

Journal of Neuroinflammation, 2015 · DOI: 10.1186/s12974-015-0440-3 · Published: November 18, 2015

Simple Explanation

Spinal cord injury triggers a macrophage response. Pro-inflammatory macrophages are neurotoxic, while anti-inflammatory macrophages promote axon growth and remyelination. Macrophages are polarized toward a pro-inflammatory phenotype after human and rodent SCI, and it is believed that these cells contribute to secondary injury processes. AZM increases alternative macrophage activation in rodent models of lung infection, skin inflammation, and sepsis; in alveolar macrophage and human monocyte cultures when incubated with pro-inflammatory stimulants; and in humans with cystic fibrosis. AZM treatment resulted in significantly increased functional recovery and less long-term tissue damage. In vitro, AZM drove anti-inflammatory cytokine production in response pro-inflammatory stimuli and rendered pro-inflammatory macrophages non-toxic.

Study Duration

4 weeks

Participants

C57BL/6J mice, 3-4 months old

Evidence Level

Not specified

Key Findings

1
SCI mice exhibited significantly increased anti-inflammatory and decreased pro-inflammatory macrophage activation in response to AZM treatment.
2
AZM treatment led to improved tissue sparing and recovery of gross and coordinated locomotor function.
3
AZM treatment altered macrophage phenotype in vitro and lowered the neurotoxic potential of pro-inflammatory, M1 macrophages.

Research Summary

AZM treatment increases macrophage expression of anti-inflammatory genes and facilitates significant improvements in SCI locomotor recovery and tissue sparing. Macrophages, purified from the injured spinal cord of mice treated with AZM, had increased expression of CD206 and arginase, indicators of an anti-inflammatory phenotype, with decreased expression of the pro-inflammatory marker CD86. AZM directly alters the phenotype and neurotoxic potential of pro-inflammatory macrophages in vitro.

Practical Implications

Therapeutic Potential

Highlights the potential for an immunomodulatory, pharmacological therapy like AZM to be an effective treatment for SCI and identifies AZM as a promising candidate for further translational development.

Clinical Viability

Given AZM's safety profile, ability to be administered chronically, and accumulation in brain tissue following oral administration, it presents as an ideal drug for treating neuroinflammatory conditions.

Broader Applicability

The neuroprotective effects of AZM could extend to other neuropathological conditions characterized by neuroinflammation and pro-inflammatory macrophage activation.

Study Limitations

1
Combined pre- and post-SCI dosing strategy.
2
The mechanisms underlying the decreased macrophage recruitment we observed remain to be elucidated.
3
The specific mechanism responsible for the immunomodulatory potential of AZM and other macrolides are not well understood.

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