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 4

Genetic or pharmacological inhibition of TRPV4 suppresses abnormal gait following SNI.

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Genetic or pharmacological inhibition of TRPV4 suppresses abnormal gait ...
(A and B) Representative footprint timing view and CatWalk gait analysis of WT mice and Trpv4–/– mice on day 7 after SNI. n = 5–6 mice per group. Statistics were determined by paired or unpaired 2-tailed Student’s t test. (C and D) Representative footprint timing view and CatWalk gait analysis of Trpv4fl/fl control littermates and Cx3cr1CreER/+:Trpv4fl/fl mice on day 7 after SNI. n = 7 mice per group. Statistics were determined by paired or unpaired 2-tailed Student’s t test. (E and F) Representative footprint timing view and CatWalk gait analysis of WT mice treated with i.p. injection of vehicle or GSK219 (30 mg/kg, once per day from day 1–7 after SNI) on day 7 after SNI. n = 7 mice per group. Statistics were determined by paired or unpaired 2-tailed Student’s t test. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.