A shed form of LDL receptor-related protein-1 regulates peripheral nerve injury and neuropathic pain in rodents.
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.
Department of Pathology, UCSD School of Medicine, La Jolla, California 92093-0629, USA.
Alban
A
Gaultier
Sanja
S
Arandjelovic
Xiaoqing
X
Li
Julie
J
Janes
Nikola
N
Dragojlovic
George P
GP
Zhou
Jenny
J
Dolkas
Robert R
RR
Myers
Steven L
SL
Gonias
W Marie
WM
Campana
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002908:Chronic Disease; D003250:Constriction; D004705:Endocytosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000302:isolation & purification / Q000378:metabolism / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D010146:Pain / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020671:Posterior Horn Cells / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology; D012584:Sciatic Nerve / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D053583:Interleukin-1beta; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases