Hevin/Sparcl1 drives pathological pain through spinal cord astrocyte and NMDA receptor signaling
Gang Chen, … , Cagla Eroglu, Ru-Rong Ji
Gang Chen, … , Cagla Eroglu, Ru-Rong Ji
Published October 18, 2022
Citation Information: JCI Insight. 2022;7(23):e161028. https://doi.org/10.1172/jci.insight.161028.
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Research Article Neuroscience

Hevin/Sparcl1 drives pathological pain through spinal cord astrocyte and NMDA receptor signaling

Abstract

High endothelial venule protein/SPARC-like 1 (hevin/Sparcl1) is an astrocyte-secreted protein that regulates synapse formation in the brain. Here we show that astrocytic hevin signaling plays a critical role in maintaining chronic pain. Compared with WT mice, hevin-null mice exhibited normal mechanical and heat sensitivity but reduced inflammatory pain. Interestingly, hevin-null mice have faster recovery than WT mice from neuropathic pain after nerve injury. Intrathecal injection of WT hevin was sufficient to induce persistent mechanical allodynia in naive mice. In hevin-null mice with nerve injury, adeno-associated-virus–mediated (AAV-mediated) re-expression of hevin in glial fibrillary acidic protein–expressing (GFAP-expressing) spinal cord astrocytes could reinstate neuropathic pain. Mechanistically, hevin is crucial for spinal cord NMDA receptor (NMDAR) signaling. Hevin-potentiated N-Methyl-D-aspartic acid (NMDA) currents are mediated by GluN2B-containing NMDARs. Furthermore, intrathecal injection of a neutralizing Ab against hevin alleviated acute and persistent inflammatory pain, postoperative pain, and neuropathic pain. Secreted hevin that was detected in mouse cerebrospinal fluid (CSF) and nerve injury significantly increased CSF hevin abundance. Finally, neurosurgery caused rapid and substantial increases in SPARCL1/HEVIN levels in human CSF. Collectively, our findings support a critical role of hevin and astrocytes in the maintenance of chronic pain. Neutralizing of secreted hevin with monoclonal Ab may provide a new therapeutic strategy for treating acute and chronic pain and NMDAR-medicated neurodegeneration.

Authors

Gang Chen, Jing Xu, Hao Luo, Xin Luo, Sandeep K. Singh, Juan J. Ramirez, Michael L. James, Joseph P. Mathew, Miles Berger, Cagla Eroglu, Ru-Rong Ji

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Figure 6

Anti-hevin monoclonal Ab 12:54 reduces inflammatory, postoperative, and neuropathic pain in WT mice.

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Anti-hevin monoclonal Ab 12:54 reduces inflammatory, postoperative, and ...
(A) ELISA analysis showing increased hevin level in the CSF 14 days after CCI. n = 5 mice/group. *P < 0.05, unpaired Student’s t test. (B) Left, time course of formalin-induced pain in WT male mice treated with intrathecal anti-hevin 12:155 monoclonal Ab (control Ab, 10 μg) or anti-hevin 12:54 monoclonal Ab (function blocking Ab, 10 μg). n = 5 mice per group. Right, formalin-induced Phase 1 and Phase 2 responses. *P < 0.05, unpaired Student’s t test. (C) Intrathecal injection of anti-hevin 12:54 Ab (10 μg), given 3 days after CFA injection, reduced CFA-induced mechanical allodynia for 5 hours. Arrows indicate the time of Ab injection. n = 5 mice/group. #P < 0.05, ##P < 0.01 versus corresponding BL group; *P < 0.05 versus anti-hevin 12:155 group, 2-way ANOVA followed by Bonferroni’s post hoc test. (D) Intrathecal injection of anti-hevin 12:54 Ab (10 μg) given 3 hours after plantar incision, reduced incision-induced mechanical allodynia for 5 hours in male and female mice. Arrows indicate the time of Ab injection. n = 10 mice/group. ###P < 0.001 versus corresponding BL group; ***P < 0.001 versus anti-hevin 12:155 group, 2-way ANOVA followed by Bonferroni’s post hoc test. (E and F) Intrathecal injection of anti-hevin 12:54 Ab (10 μg), given 7 days E and 21 days F after nerve injury, reduced CCI-induced mechanical allodynia for 5 hours. Arrows indicate the time of Ab injection. n = 5–6 mice/group. #P < 0.05 versus corresponding BL group; §P < 0.05, §§P < 0.01 versus corresponding baseline at CCI 7 days or CCI 21 days; *P < 0.05, **P < 0.01, 2-way ANOVA followed by Bonferroni’s post hoc test. Data are shown as mean ± SEM.