The low-density lipoprotein receptor-related protein is a pro-survival receptor in Schwann cells: possible implications in peripheral nerve injury

WM Campana, X Li, N Dragojlovic, J Janes… - Journal of …, 2006 - Soc Neuroscience
WM Campana, X Li, N Dragojlovic, J Janes, A Gaultier, SL Gonias
Journal of Neuroscience, 2006Soc Neuroscience
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 …
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-α (TNF-α) was mostly responsible for the increase in LRP-1 expression; this activity was reproduced by direct injection of TNF-α into injured nerves in the TNF-α gene knock-out mouse. TNF receptor II was primarily involved. TNF-α 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-α, 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.
Soc Neuroscience