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A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain
Xueming Hu, … , Gregory F. Wu, Hongzhen Hu
Xueming Hu, … , Gregory F. Wu, Hongzhen Hu
Published January 26, 2023
Citation Information: J Clin Invest. 2023;133(5):e161507. https://doi.org/10.1172/JCI161507.
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Research Article Neuroscience Article has an altmetric score of 20

A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain

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Abstract

Microglia, resident macrophages of the CNS, are essential to brain development, homeostasis, and disease. Microglial activation and proliferation are hallmarks of many CNS diseases, including neuropathic pain. However, molecular mechanisms that govern the spinal neuroimmune axis in the setting of neuropathic pain remain incompletely understood. Here, we show that genetic ablation or pharmacological blockade of transient receptor potential vanilloid type 4 (TRPV4) markedly attenuated neuropathic pain-like behaviors in a mouse model of spared nerve injury. Mechanistically, microglia-expressed TRPV4 mediated microglial activation and proliferation and promoted functional and structural plasticity of excitatory spinal neurons through release of lipocalin-2. Our results suggest that microglial TRPV4 channels reside at the center of the neuroimmune axis in the spinal cord, which transforms peripheral nerve injury into central sensitization and neuropathic pain, thereby identifying TRPV4 as a potential new target for the treatment of chronic pain.

Authors

Xueming Hu, Lixia Du, Shenbin Liu, Zhou Lan, Kaikai Zang, Jing Feng, Yonghui Zhao, Xingliang Yang, Zili Xie, Peter L. Wang, Aaron M. Ver Heul, Lvyi Chen, Vijay K. Samineni, Yan-Qing Wang, Kory J. Lavine, Robert W. Gereau IV, Gregory F. Wu, Hongzhen Hu

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Figure 6

TRPV4 is necessary and sufficient for nerve injury–induced microgliosis following SNI.

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TRPV4 is necessary and sufficient for nerve injury–induced microgliosis ...
(A and B) Representative images of CX3CR1-GFP and EdU coexpression in spinal dorsal horn (A) and quantification of MFI of CX3CR1-GFP and number of EdU+/CX3CR1-GFP+ microglia from Cx3cr1GFP/+ and Cx3cr1GFP/+:Trpv4–/– mice on day 7 after SNI (B). (C and D) Representative images of CX3CR1-tdTomato and EdU coexpression in spinal dorsal horn (C) and quantification of MFI of CX3CR1-tdTomato and number of EdU+/CX3CR1-tdTomato+ microglia from Cx3cr1CreER/+:tdTomato:+/+ and Cx3cr1CreER/+:tdTomato:Trpv4fl/fl mice on day 7 after SNI (D). EdU was i.p. administrated once per day for 3 consecutive days starting on day 1 after SNI. n = 20 spinal slices from 4 mice per group. ***P < 0.001 by unpaired 2-tailed Student’s t test. Scale bar: 200 μm. (E and F) Representative images of CX3CR1-tdTomato and EdU coexpression in spinal dorsal horn (E) and quantification of the MFI of CX3CR1-tdTomato and number of EdU+/CX3CR1-tdTomato+ microglia from Cx3cr1GFP/+ mice following GSK101 administration (F). Coadministration of i.t. GSK101 (1 μg) and i.p. EdU injection was performed once per day for 3 consecutive days. n = 20 spinal slices from 4 mice per group. ***P < 0.001 by unpaired 2-tailed Student’s t test. Scale bars: 100 μm and 20 μm (zoom). Data are presented as mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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