Low-density lipoprotein receptor-related protein 1 is an essential receptor for myelin phagocytosis
Author:
Gaultier Alban1, Wu Xiaohua2, Le Moan Natacha34, Takimoto Shinako1, Mukandala Gatambwa1, Akassoglou Katerina34, Campana W. Marie5, Gonias Steven L.1
Affiliation:
1. Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA 2. The McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Charlotte, NC 28203, USA 3. Gladstone Institute of Neurological Diseases, University of California, San Francisco, San Francisco, CA 94158, USA 4. Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA 5. Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA
Abstract
Multiple sclerosis (MS) is an autoimmune disease in which myelin is progressively degraded. Because degraded myelin may both initiate and accelerate disease progression, clearing degraded myelin from extracellular spaces may be critical. In this study, we prepared myelin vesicles (MV) from rat brains as a model of degraded myelin. Murine embryonic fibroblasts (MEFs) rapidly internalized MVs, which accumulated in lysosomes only when these cells expressed low-density lipoprotein receptor-related protein (LRP1). Receptor-associated protein (RAP), which binds LRP1 and inhibits interaction with other ligands, blocked MV uptake by LRP1-expressing MEFs. As a complementary approach, we prepared primary cultures of rat astrocytes, microglia and oligodendrocytes. All three cell types expressed LRP1 and mediated MV uptake, which was inhibited by RAP. LRP1 gene-silencing in oligodendrocytes also blocked MV uptake. Myelin basic protein (MBP), which was expressed as a recombinant protein, bound directly to LRP1. MBP-specific antibody inhibited MV uptake by oligodendrocytes. In experimental autoimmune encephalomyelitis in mice, LRP1 protein expression was substantially increased in the cerebellum and spinal cord. LRP1 colocalized with multiple CNS cell types. These studies establish LRP1 as a major receptor for phagocytosis of degraded myelin, which may function alone or in concert with co-receptors previously implicated in myelin phagocytosis.
Publisher
The Company of Biologists
Reference55 articles.
1. Adams, R. A., Bauer, J., Flick, M. J., Sikorski, S. L., Nuriel, T., Lassmann, H., Degen, J. L. and Akassoglou, K. (2007). The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J. Exp. Med.204, 571-582. 2. Akassoglou, K., Douni, E., Bauer, J., Lassmann, H., Kollias, G. and Probert, L. (2003). Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice. Proc. Natl. Acad. Sci. USA100, 709-714. 3. An, J., Zhang, C., Polavarapu, R., Zhang, X., Zhang, X. and Yepes, M. (2008). Tissue-type plasminogen activator and the low density lipoprotein receptor-related protein induce Akt phosphorylation in the ischemic brain. Blood112, 2787-2794. 4. Antony, J. M., van Marle, G., Opii, W., Butterfield, D. A., Mallet, F., Yong, V. W., Wallace, J. L., Deacon, R. M., Warren, K. and Power, C. (2004). Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat. Neurosci.7, 1088-1095. 5. Arnold-Schild, D., Hanau, D., Spehner, D., Schmid, C., Rammensee, H. G., de la Salle, H. and Schild, H. (1999). Cutting edge: receptor-mediated endocytosis of heat shock proteins by professional antigen-presenting cells. J. Immunol.162, 3757-3760.
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