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- Title
A shed form of LDL receptor-related protein-1 regulates peripheral nerve injury and neuropathic pain in rodents.
- Authors
Gaultier, Alban; Arandjelovic, Sanja; Li, Xiaoqing; Janes, Julie; Dragojlovic, Nikola; Zhou, George P; Dolkas, Jenny; Myers, Robert R; Gonias, Steven L; Campana, W Marie
- Abstract
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 alpha-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-1beta 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.
- Publication
The Journal of clinical investigation, 2008, Vol 118, Issue 1, p161
- ISSN
0021-9738
- Publication type
Journal Article
- DOI
10.1172/JCI32371