Abstract
Spinal cord injury (SCI) triggers a heterogeneous macrophage response that when experimentally polarized toward alternative forms of activation (M2 macrophages) promotes tissue and functional recovery. There are limited pharmacological therapies that can drive this reparative inflammatory state. In the current study, we used in vitro systems to comprehensively defined markers of macrophages with known pathological (M1) and reparative (M2) properties in SCI. We then used these markers to objectively define the macrophage activation states after SCI in response to delayed azithromycin treatment. Mice were subjected to moderate-severe thoracic contusion SCI. Azithromycin or vehicle was administered beginning 30 minutes post-SCI and then daily for 3 or 7 days post injury (dpi). We detected a dose-dependent polarization toward purportedly protective M2 macrophages with daily AZM treatment. Specifically, AZM doses of 10, 40, or 160 mg/kg decreased M1 macrophage gene expression at 3 dpi while the lowest (10 mg/kg) and highest (160 mg/kg) doses increased M2 macrophage gene expression at 7 dpi. Azithromycin has documented immunomodulatory properties and is commonly prescribed to treat infections in SCI individuals. This work demonstrates the utility of objective, comprehensive macrophage gene profiling for evaluating immunomodulatory SCI therapies and highlights azithromycin as a promising agent for SCI treatment.
Highlights
Spinal cord injury (SCI) activates CNS macrophages consisting of endogenous microglia and recruited monocyte-derived macrophages
The purpose of this study was to determine if AZM treatment, initiated after SCI, alters the macrophage response to injury
Since we previously observed that the response of bone marrow-derived macrophages (BMDM) in vitro is predictive of SCI macrophages in vivo[1,28], we used the genes presented in Fig. 2 as an objective, unbiased, a priori means of phenotyping M1 and M2 macrophages in SCI
Summary
Spinal cord injury (SCI) activates CNS macrophages consisting of endogenous microglia and recruited monocyte-derived macrophages These cells have pathological properties and contribute to neurodegeneration and tissue loss subsequent to the initial mechanical trauma. The goal of the current work was to test the immunomodulatory potential and dose-response of AZM treatment initiated after experimental SCI. We used small-scale gene array to identify a comprehensive set of genetic markers to identify macrophages with published pathological (M1) and reparative properties (M2) for SCI. We used these markers to objectively determine the dose-response and efficacy of post-SCI AZM treatment
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