A shed form of LDL receptor-related protein-1 regulates peripheral nerve injury and neuropathic pain in rodents
A shed form of LDL receptor-related protein-1 regulates peripheral nerve injury and neuropathic pain in rodents
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DOI：
10.1172/jci32371
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发表时间：
2008-01-01
影响因子：
15.9
通讯作者：
Campana, W. Marie
中科院分区：
文献类型：
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作者：
Gaultier, Alban;Arandjelovic, Sanja;Campana, W. Marie
周围神经系统 (PNS) 损伤会引发由多种细胞外介质控制的反应，其中许多介质会导致神经性疼痛的发生。受损神经中的雪旺细胞表现出 LDL 受体相关蛋白 1 (LRP1) 的表达增加，LRP1 是多种配体的内吞受体和细胞存活因子。在这里，我们报道了 LRP1 的一个片段，其中具有完整 a 链的可溶或脱落形式的 LRP1 (sLRP-α)，在体外和损伤后的三七总皂甙中被雪旺细胞脱落。在慢性缩窄性损伤 (CCI) 之前将纯化的 sLRP-α 注射到小鼠坐骨神经中，可抑制 p38 MAPK 激活 (P-p38)，并局部降低 TNF-α 和 IL-1 β 的表达。 sLRP-α 还抑制 CCI 诱导的自发性神经性疼痛，并减少脊髓背角（神经性疼痛处理发生的地方）中炎症细胞因子的表达。在雪旺细胞、星形胶质细胞和小胶质细胞的培养物中，sLRP-α 抑制 TNF-α 诱导的 p38 MAPK 和 ERK/MAPK 激活。 sLRP-α的活性并不涉及TNF-α结合，而是涉及神经胶质细胞的预处理，从而抑制随后对TNF-α的反应。我们的结果表明 sLRP-alpha 具有生物活性，可以减轻神经性疼痛。在PNS中，LRP1的功能可能反映了膜锚定型和脱落型LRP1的综合活性。
Injury to the peripheral nervous system (PNS) initiates a response controlled by multiple extracellular mediators, many of which contribute to the development of neuropathic pain. Schwann cells in an injured nerve demonstrate increased expression of LDL receptor-related protein-1 (LRP1), an endocytic receptor for diverse ligands and a cell survival factor. Here we report that a fragment of LRP1, in which a soluble or shed form of LRP1 with an intact a-chain (sLRP-alpha), was shed by Schwann cells in vitro and in the PNS after injury. Injection of purified sLRP-alpha into mouse sciatic nerves prior to chronic constriction injury (CCI) inhibited p38 MAPK activation (P-p38) and decreased expression of TNF-alpha and IL-1 beta locally. sLRP-alpha also inhibited CCI-induced spontaneous neuropathic pain and decreased inflammatory cytokine expression in the spinal dorsal horn, where neuropathic pain processing occurs. in cultures of Schwann cells, astrocytes, and microglia, sLRP-alpha inhibited TNF-alpha-induced activation of p38 MAPK and ERK/MAPK. The activity of sLRP-alpha did not involve TNF-alpha binding, but rather glial cell preconditioning, so that the subsequent response to TNF-alpha was inhibited. Our results show that sLRP-alpha is biologically active and may attenuate neuropathic pain. In the PNS, the function of LRP1 may reflect the integrated activities of the membrane-anchored and shed forms of LRP1.