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

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 9

TRPV4 is necessary and sufficient for LCN2 expression in the spinal microglia.

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TRPV4 is necessary and sufficient for LCN2 expression in the spinal micr...
(A) Representative images of LCN2 antibody with CX3CR1-tdTomato in the spinal dorsal horn of Cx3cr1CreER/+:tdTomato mice on day 7 after SNI. Scale bars: 100 μm and 20 μm (zoom). (B and C) Relative expression levels of Lcn2 mRNA in the ipsilateral sides of the spinal cord from WT mice and Trpv4–/– mice (B), Trpv4fl/fl control littermates and Cx3cr1CreER/+:Trpv4fl/fl mice (C) on day 7 after sham or SNI surgery. n = 6 mice per group. Statistics were determined by 1-way ANOVA with Bonferroni’s post hoc test. (D and E) Relative expression levels of Lcn2 mRNA in the cultured primary spinal microglia (D) and LCN2 release in the culture supernates (E) with GSK101 (300 nM) and GSK219 (30 nM) treatment. n = 4 wells per group from 2 independent experiments. Statistics were determined by 1-way ANOVA with Bonferroni’s post hoc test. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.