Abstract
BackgroundLarge-scale macrophage infiltration and reactive astrogliosis are hallmarks of early spinal cord injury (SCI) pathology. The exact nature of the macrophage response and relationship between these phenomena have not been explored in detail. Here, we have investigated these responses using a combination of in vivo SCI models, organotypic and primary cultures.MethodsIn vivo macrophage response was investigated using a contusive injury mouse model. Interactions between astrocytes and macrophages were studied in primary or organotypic cultures. Proliferation was assessed though MTT assay and nucleotide incorporation and gene expression changes through qPCR.ResultsSeven days following contusive SCI, a mixed M1/M2 macrophage response was seen in the injury site. Conditioned medium from primary M1, but not M2, macrophages are able to induce astrocyte proliferation in both organotypic spinal cord cultures and primary astrocytes. Soluble factors from M1 macrophages induce a reactive astrocyte gene expression pattern, whereas M2 factors inhibit expression of these genes. M2-stimulated astrocytes are also able to decrease both M1 and M2 macrophage proliferation and decrease TNFα production in M1 macrophages.ConclusionsThese results suggest a strong role of M1 macrophages in inducing reactive astrogliosis and the existence of an astrocyte-mediated negative feedback system in order to dampen the immune response. These results, combined with the poor outcomes of the current immunosuppressive steroid treatments in SCI, indicate the need for more targeted therapies, taking into account the significantly different effects of M1 and M2 macrophages, in order to optimise outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0327-3) contains supplementary material, which is available to authorized users.
Highlights
Large-scale macrophage infiltration and reactive astrogliosis are hallmarks of early spinal cord injury (SCI) pathology
We aim to investigate the macrophage response to SCI and the interaction between macrophages and astrocytes to elucidate the role these play in the development of the glial scar
We report that M1 macrophages, present in significant numbers following SCI, are able to induce both astrocyte proliferation and a reactive phenotype, which can be partially counteracted by M2 macrophages
Summary
Large-scale macrophage infiltration and reactive astrogliosis are hallmarks of early spinal cord injury (SCI) pathology. Following SCI, the initial phagocytotic response is from the resident microglia, as the blood–brain barrier is generally compromised following SCI, peripheral macrophages rapidly infiltrate the spinal cord and become the predominant phagocytosing cell type at 3 days post injury (dpi) [4] in mouse models. In an experimental demyelination model in the brain, M2 type macrophages were required for initiation of remyelination [10], and it has been suggested that M2 macrophages are neurosupportive in SCI as well [11] This indicates a potential regenerative role for these cells in the nervous system. There have been several reports about the exact nature of the macrophage response in SCI, with varying propor-tions of M1 and M2 having been described [11,12,13,14,15]. How these macrophage phenotypical differences affect the development and resolution of SCI is still unclear
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