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Chemokine expression by astrocytes plays a role in microglia/macrophage activation and subsequent neurodegeneration in secondary progressive multiple sclerosis

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Abstract

The pathological hallmarks of secondary progressive (SP) multiple sclerosis (MS) include slowly expanding demyelination and axonal damage with less inflammation. To elucidate the pathomechanisms of secondary progressive (SP) multiple sclerosis (MS), we have investigated the expression of chemokines, chemokine receptors, matrix metalloproteinase-9 (MMP-9) and immunoglobulins in the demyelinating plaques. Immunohistochemical analysis revealed that numerous hypertrophic astrocytes were observed at the rim, but not in the center, of the chronic active lesions. Microglia/macrophages phagocytosing myelin debris were also found at the lesion border. In contrast, T cell infiltration was minimal in these plaques. Characteristically, at the rim of the lesions, there were abundant immunoreactivities for monocyte chemoattractant protein-1 (MCP-1)/CCL2 and interferon-γ inducible protein-10 (IP-10)/CXCL10 and their receptors, CCR2 and CXCR3, while these immunoreactivities were weak in the center, thus forming a chemokine gradient. Double immunofluorescense staining demonstrated that cellular sources of MCP-1/CCL2 and IP-10/CXCL10 were hypertrophic astrocytes and that both astrocytes and microglia/macrophages expressed CCR2 and CXCR3. MMP-9 was also present at the rim of the lesions. These results suggest that MCP-1/CCL2 and IP-10/CXCL10 produced by astrocytes may activate astrocytes in an autocrine or paracrine manner and direct reactive gliosis followed by migration and activation of microglia/macrophages as effector cells in demyelinating lesions. Targeting chemokines in SPMS may therefore be a powerful therapeutic approach to inhibit lesional expansion.

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Acknowledgments

The authors thank Yoko Kawazoe for technical assistance. MS brain tissue samples were supplied by the UK Multiple Sclerosis Tissue Bank. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Authors and Affiliations

  1. Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, 2-6, Musashidai, Fuchu, Tokyo, 183-8526, Japan

    Naoyuki Tanuma, Hiroshi Sakuma & Yoh Matsumoto

  2. Department of Human Pathology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Atsushi Sasaki

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  1. Naoyuki Tanuma
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Correspondence to Yoh Matsumoto.

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Tanuma, N., Sakuma, H., Sasaki, A. et al. Chemokine expression by astrocytes plays a role in microglia/macrophage activation and subsequent neurodegeneration in secondary progressive multiple sclerosis. Acta Neuropathol 112, 195–204 (2006). https://doi.org/10.1007/s00401-006-0083-7

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  • DOI: https://doi.org/10.1007/s00401-006-0083-7

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