Azithromycin drives alternative macrophage activation and improves recovery and tissue sparing in contusion spinal cord injuryReport as inadecuate




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Journal of Neuroinflammation

, 12:218

First Online: 24 November 2015Received: 17 July 2015Accepted: 18 November 2015

Abstract

BackgroundMacrophages persist indefinitely at sites of spinal cord injury SCI and contribute to both pathological and reparative processes. While the alternative, anti-inflammatory M2 phenotype is believed to promote cell protection, regeneration, and plasticity, pro-inflammatory M1 macrophages persist after SCI and contribute to protracted cell and tissue loss. Thus, identifying non-invasive, clinically viable, pharmacological therapies for altering macrophage phenotype is a challenging, yet promising, approach for treating SCI. Azithromycin AZM, a commonly used macrolide antibiotic, drives anti-inflammatory macrophage activation in rodent models of inflammation and in humans with cystic fibrosis.

MethodsWe hypothesized that AZM treatment can alter the macrophage response to SCI and reduce progressive tissue pathology. To test this hypothesis, mice C57BL-6J, 3-month-old received daily doses of AZM 160 mg-kg or vehicle treatment via oral gavage for 3 days prior and up to 7 days after a moderate-severe thoracic contusion SCI 75-kdyn force injury. Fluorescent-activated cell sorting was used in combination with real-time PCR rtPCR to evaluate the disposition and activation status of microglia, monocytes, and neutrophils, as well as macrophage phenotype in response to AZM treatment. An open-field locomotor rating scale Basso Mouse Scale and gridwalk task were used to determine the effects of AZM treatment on SCI recovery. Bone marrow-derived macrophages BMDMs were used to determine the effect of AZM treatment on macrophage phenotype in vitro.

ResultsIn accordance with our hypothesis, SCI mice exhibited significantly increased anti-inflammatory and decreased pro-inflammatory macrophage activation in response to AZM treatment. In addition, AZM treatment led to improved tissue sparing and recovery of gross and coordinated locomotor function. Furthermore, AZM treatment altered macrophage phenotype in vitro and lowered the neurotoxic potential of pro-inflammatory, M1 macrophages.

ConclusionsTaken together, these data suggest that pharmacologically intervening with AZM can alter SCI macrophage polarization toward a beneficial phenotype that, in turn, may potentially limit secondary injury processes. Given that pro-inflammatory macrophage activation is a hallmark of many neurological pathologies and that AZM is non-invasive and clinically viable, these data highlight a novel approach for treating SCI and other maladaptive neuroinflammatory conditions.

KeywordsMacrolide antibiotic Spinal cord injury Alternatively activated Macrophage Microglia Azithromycin M1 M2 Bei Zhang and William M. Bailey contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s12974-015-0440-3 contains supplementary material, which is available to authorized users.

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Author: Bei Zhang - William M. Bailey - Timothy J. Kopper - Michael B. Orr - David J. Feola - John C. Gensel

Source: https://link.springer.com/



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