A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents
Alban Gaultier, Sanja Arandjelovic, Xiaoqing Li, Julie Janes, Nikola Dragojlovic, George P. Zhou, Jenny Dolkas, Robert R. Myers, Steven L. Gonias, W. Marie Campana
Alban Gaultier, Sanja Arandjelovic, Xiaoqing Li, Julie Janes, Nikola Dragojlovic, George P. Zhou, Jenny Dolkas, Robert R. Myers, Steven L. Gonias, W. Marie Campana
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Research Article

A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

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 α-chain (sLRP-α), was shed by Schwann cells in vitro and in the PNS after injury. Injection of purified sLRP-α into mouse sciatic nerves prior to chronic constriction injury (CCI) inhibited p38 MAPK activation (P-p38) and decreased expression of TNF-α and IL-1β locally. sLRP-α 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-α inhibited TNF-α–induced activation of p38 MAPK and ERK/MAPK. The activity of sLRP-α did not involve TNF-α binding, but rather glial cell preconditioning, so that the subsequent response to TNF-α was inhibited. Our results show that sLRP-α 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.

Authors

Alban Gaultier, Sanja Arandjelovic, Xiaoqing Li, Julie Janes, Nikola Dragojlovic, George P. Zhou, Jenny Dolkas, Robert R. Myers, Steven L. Gonias, W. Marie Campana

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Figure 8

sLRP-α antagonizes TNF-α–initiated cell signaling in astrocytes and microglia.

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sLRP-α antagonizes TNF-α–initiated cell signaling in astrocytes and micr...
(A) Astrocyte cultures are immunopositive for GFAP (anti-GFAP, red). Cell nuclei were stained with DAPI (blue). (B) Astrocytes were cultured in serum-free medium for 1 h to reduce the basal level of activation of ERK/MAPK. The cells were then treated with TNF-α (1 nM) or vehicle for 10 min. Cell extracts were subjected to immunoblot analysis to detect P-ERK1/2 and T-ERK1/2. Some cells were pretreated with vehicle or sLRP-α (50 nM) for 10 min prior to adding TNF-α (1.0 nM) for 10 min. The blot is representative of 2 independent studies. (C) Microglial cell cultures were immunopositive for the complement receptor CR3, as determined with antibody OX-42 (green). Cell nuclei were stained with DAPI (blue). (D) Microglia were pretreated with vehicle of sLRP-α for 10 min and then treated with TNF-α (1.0 nM). Extracts were subjected to immunoblot analysis to detect P-p38. β-Actin was used as a loading control.