The low-density lipoprotein receptor-related protein is a pro-survival receptor in Schwann cells: possible implications in peripheral nerve injury.
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.
Campana
W Marie
WM
Department of Anesthesiology, University of California, San Diego School of Medicine, La Jolla, California 92093-0629, USA. wcampana@ucsd.edu
Li
Xiaoqing
X
Dragojlovic
Nikola
N
Janes
Julie
J
Gaultier
Alban
A
Gonias
Steven L
SL
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D005260:Female; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000096:biosynthesis* / Q000235:genetics; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology; D020426:Sciatic Neuropathy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D012333:RNA, Messenger; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins