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The Journal of Neuroscience, October 25, 2006, 26(43):11197-11207; doi:10.1523/JNEUROSCI.2709-06.2006

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Cellular/Molecular
The Low-Density Lipoprotein Receptor-Related Protein Is a Pro-Survival Receptor in Schwann Cells: Possible Implications in Peripheral Nerve Injury

W. Marie Campana,1 Xiaoqing Li,1 Nikola Dragojlovic,2 Julie Janes,1 Alban Gaultier,2 and Steven L. Gonias2

1Departments of Anesthesiology and 2Pathology, University of California, San Diego School of Medicine, La Jolla, California 92093-0629

Correspondence should be addressed to Dr. W. Marie Campana, Department of Anesthesiology (0629), University of California, San Diego, 9500 Gilman Drive, MTF 445, La Jolla, CA 92093-0629. Email: wcampana{at}ucsd.edu

Schwann cells undergo phenotypic modulation in peripheral nerve injury. In the adult rodent, Schwann cells are resistant to death-promoting challenges. The responsible receptors and signaling pathways are incompletely understood. In this study, we demonstrate that low-density lipoprotein receptor-related protein-1 (LRP-1) is expressed in adult sciatic nerve. After crush injury, LRP-1 is lost from the axoplasm and substantially upregulated in Schwann cells. Increased LRP-1 mRNA expression was observed locally at the injury site in multiple forms of sciatic nerve injury, including crush injury, chronic constriction injury, and axotomy. Endogenously produced tumor necrosis factor-{alpha} (TNF-{alpha}) was mostly responsible for the increase in LRP-1 expression; this activity was reproduced by direct injection of TNF-{alpha} into injured nerves in the TNF-{alpha} gene knock-out mouse. TNF receptor II was primarily involved. TNF-{alpha} also increased LRP-1 mRNA in Schwann cells in primary culture. Silencing of Schwann cell LRP-1 with siRNA decreased phosphorylated Akt and increased activated caspase-3. Equivalent changes in cell signaling were observed in LRP-1-deficient murine embryonic fibroblasts. Schwann cell death was induced in vitro by serum withdrawal or TNF-{alpha}, to a greater extent when LRP-1 was silenced. Schwann cell death was induced in vivo by injecting the LRP-1 antagonist, receptor-associated protein, into axotomy sites in adult rats. These results support a model in which LRP-1 functions as a pro-survival receptor in Schwann cells.

Key words: Schwann cell; peripheral nerve injury; low-density lipoprotein receptor-related protein; tumor necrosis factor-{alpha}; apoptosis; phosphatidylinositol 3-kinase

Received March 31, 2006; revised Sept. 13, 2006; accepted Sept. 17, 2006.

Correspondence should be addressed to Dr. W. Marie Campana, Department of Anesthesiology (0629), University of California, San Diego, 9500 Gilman Drive, MTF 445, La Jolla, CA 92093-0629. Email: wcampana{at}ucsd.edu




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