Campana W Marie, Li Xiaoqing, Dragojlovic Nikola, Janes Julie, Gaultier Alban, Gonias Steven L
Department of Anesthesiology, University of California, San Diego School of Medicine, La Jolla, California 92093-0629, USA.
J Neurosci. 2006 Oct 25;26(43):11197-207. doi: 10.1523/JNEUROSCI.2709-06.2006.
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.
雪旺细胞在外周神经损伤时会发生表型调节。在成年啮齿动物中，雪旺细胞对促死亡刺激具有抗性。其相关的受体和信号通路尚未完全明确。在本研究中，我们证明低密度脂蛋白受体相关蛋白1（LRP - 1）在成年坐骨神经中表达。挤压损伤后，LRP - 1从轴浆中消失，并在雪旺细胞中显著上调。在多种形式的坐骨神经损伤（包括挤压伤、慢性压迫性损伤和轴突切断术）的损伤部位局部观察到LRP - 1 mRNA表达增加。内源性产生的肿瘤坏死因子-α（TNF - α）是LRP - 1表达增加的主要原因；在TNF - α基因敲除小鼠中，将TNF - α直接注射到损伤神经中可重现这种活性。主要涉及TNF受体II。TNF - α也增加了原代培养的雪旺细胞中LRP - 1 mRNA的表达。用小干扰RNA沉默雪旺细胞LRP - 1可降低磷酸化的Akt并增加活化的半胱天冬酶-3。在LRP - 1缺陷的小鼠胚胎成纤维细胞中观察到细胞信号传导的等效变化。血清撤除或TNF - α在体外诱导雪旺细胞死亡，当LRP - 1沉默时，诱导程度更大。通过将LRP - 1拮抗剂受体相关蛋白注射到成年大鼠的轴突切断部位，在体内诱导雪旺细胞死亡。这些结果支持了一种模型，即LRP - 1在雪旺细胞中作为一种促存活受体发挥作用。
