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Cited by 149Epilepsy research and treatmentNeuroinflammation and Neurodegeneration MechanismsIon Channels and Receptors

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TRPV4-induced inflammatory response is involved in neuronal death in pilocarpine model of temporal lobe epilepsy in mice

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Wang, Zhouqing, Zhou, Li, An, Dong, Xu, Weixing, Wu, Chunfeng, Sha, Sha, Li, Yingchun, Zhu, Yichao, Chen, Aidong, Du, Yimei, Chen, Lei, Chen, Ling·2019·Cell Death & Disease
DOI 10.1038/s41419-019-1612-3PMC PMC6522539
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Abstract

Activation of transient receptor potential vanilloid 4 (TRPV4) induces neuronal injury. TRPV4 activation enhances inflammatory response and promotes the proinflammatory cytokine release in various types of tissue and cells. Hyperneuroinflammation contributes to neuronal damage in epilepsy. Herein, we examined the contribution of neuroinflammation to TRPV4-induced neurotoxicity and its involvement in the inflammation and neuronal damage in pilocarpine model of temporal lobe epilepsy in mice. Icv. injection of TRPV4 agonist GSK1016790A (GSK1016790A-injected mice) increased ionized calcium binding adapter molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP) protein levels and Iba-1-positive (Iba-1+) and GFAP-positive (GFAP+) cells in hippocampi, which indicated TRPV4-induced microglial cell and astrocyte activation. The protein levels of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome components NLRP3, apoptosis-related spotted protein (ASC) and cysteinyl aspartate-specific protease-1 (caspase-1) were increased in GSK1016790A-injected mice, which indicated NLRP3 inflammasome activation. GSK1016790A also increased proinflammatory cytokine IL-1β, TNF-α and IL-6 protein levels, which were blocked by caspase-1 inhibitor Ac-YVAD-cmk. GSK1016790A-induced neuronal death was attenuated by Ac-YVAD-cmk. Icv. injection of TRPV4-specific antagonist HC-067047 markedly increased the number of surviving cells 3 d post status epilepticus in pilocarpine model of temporal lobe epilepsy in mice (pilocarpine-induced status epilepticus, PISE). HC-067047 also markedly blocked the increase in Iba-1 and GFAP protein levels, as well as Iba-1+ and GFAP+ cells 3 d post-PISE. Finally, the increased protein levels of NLRP3, ASC and caspase-1 as well as IL-1β, TNF-α and IL-6 were markedly blocked by HC-067047. We conclude that TRPV4-induced neuronal death is mediated at least partially by enhancing the neuroinflammatory response, and this action is involved in neuronal injury following status epilepticus.

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Fig. 1 TRPV4 agonist induces microglial cell and astrocyte activation. a, b Icv. of TRPV4 agonist GSK1016790A markedly increased the protein levels of Iba-1 (a) and GFAP (b) in hippocampi. c, d The numbers of total and activated Iba-1+ (c, black arrow) and GFAP+ cells (d, red arrow) in hippocampal CA1 and CA3 areas in control and GSK1016790A-injected mice. Iba-1+ and GFAP+ cells (inset) in GSK1016790A-injected mice reflect the activation state of microglia and astrocyte. Scale bar = 50 μm **P < 0.01 vs. control
Fig. 1 TRPV4 agonist induces microglial cell and astrocyte activation. a, b Icv. of TRPV4 agonist GSK1016790A markedly increased the protein levels of Iba-1 (a) and GFAP (b) in hippocampi. c, d The numbers of total and activated Iba-1+ (c, black arrow) and GFAP+ cells (d, red arrow) in hippocampal CA1 and CA3 areas in control and GSK1016790A-injected mice. Iba-1+ and GFAP+ cells (inset) in GSK1016790A-injected mice reflect the activation state of microglia and astrocyte. Scale bar = 50 μm **P < 0.01 vs. controlCC BY · PubMed Central
Fig. 2 TRPV4 agonist increases NRLP3 inflammasome expression and proinflammatory cytokine production. a–c The hippocampal protein levels of NLRP3 (a), ASC (b) and caspase-1 (c) in control and GSK1016790A-injected mice. **P < 0.01 vs. control. d–f Icv. of TRPV4 agonist GSK1016790A markedly increased the protein levels of IL-1β (d), TNF-α (e) and IL-6 (f) in hippocampi. Caspase-1 specific inhibitor Ac-YVAD-cmk completely blocked the increased level of IL-1β and partially attenuated the increased levels of TNF-α and IL-6. **P < 0.01 vs. control, ##P < 0.01 vs. GSK1016790A, $P < 0.05 vs. Ac-YVAD-cmk. g Ac-YVAD-cmk markedly attenuated the GSK1016790A-induced decrease in surviving cells in hippocampal CA1 and CA3 areas. Scale bar = 50 μm **P < 0.01 vs. control, ##P < 0.01 vs. GSK1016790A, $P < 0.05 vs. Ac-YVAD-cmk
Fig. 2 TRPV4 agonist increases NRLP3 inflammasome expression and proinflammatory cytokine production. a–c The hippocampal protein levels of NLRP3 (a), ASC (b) and caspase-1 (c) in control and GSK1016790A-injected mice. **P < 0.01 vs. control. d–f Icv. of TRPV4 agonist GSK1016790A markedly increased the protein levels of IL-1β (d), TNF-α (e) and IL-6 (f) in hippocampi. Caspase-1 specific inhibitor Ac-YVAD-cmk completely blocked the increased level of IL-1β and partially attenuated the increased levels of TNF-α and IL-6. **P < 0.01 vs. control, ##P < 0.01 vs. GSK1016790A, $P < 0.05 vs. Ac-YVAD-cmk. g Ac-YVAD-cmk markedly attenuated the GSK1016790A-induced decrease in surviving cells in hippocampal CA1 and CA3 areas. Scale bar = 50 μm **P < 0.01 vs. control, ##P < 0.01 vs. GSK1016790A, $P < 0.05 vs. Ac-YVAD-cmkCC BY · PubMed Central
Fig. 3 TRPV4 antagonist attenuates neuronal death and activation of microglial cell and astrocyte post-PISE. a TRPV4 antagonist HC-067047 markedly increased the number of surviving cells post-PISE. Scale bar = 50 μm &&P < 0.01 vs. control, ~~P < 0.01 vs. PISE, $$P < 0.01 vs. control, ▲P < 0.05, ▲▲P < 0.01 vs. HC-067047. b, c HC-067047 decreased Iba-1 (b) and GFAP (c) protein levels post-PISE. &&P < 0.01 vs. control, ~~P < 0.01 vs. PISE. d, e HC-067047 attenuated the total and activated numbers of Iba-1+ (d) and GFAP+ cells (e) post-PISE. Scale bar = 50 μm &&P < 0.01 vs. control, ~~P < 0.01 vs. PISE, ▲P < 0.05, ▲▲P < 0.01 vs. HC-067047
Fig. 3 TRPV4 antagonist attenuates neuronal death and activation of microglial cell and astrocyte post-PISE. a TRPV4 antagonist HC-067047 markedly increased the number of surviving cells post-PISE. Scale bar = 50 μm &&P < 0.01 vs. control, ~~P < 0.01 vs. PISE, $$P < 0.01 vs. control, ▲P < 0.05, ▲▲P < 0.01 vs. HC-067047. b, c HC-067047 decreased Iba-1 (b) and GFAP (c) protein levels post-PISE. &&P < 0.01 vs. control, ~~P < 0.01 vs. PISE. d, e HC-067047 attenuated the total and activated numbers of Iba-1+ (d) and GFAP+ cells (e) post-PISE. Scale bar = 50 μm &&P < 0.01 vs. control, ~~P < 0.01 vs. PISE, ▲P < 0.05, ▲▲P < 0.01 vs. HC-067047CC BY · PubMed Central
Fig. 4 TRPV4 antagonist decreases NLRP3 inflammasome expression and proinflammatory cytokine production post-PISE. a–c Increased hippocampal protein levels of NLRP3 (a), ASC (b) and caspase-1 (c) post-PISE were markedly attenuated by HC-067047. &&P < 0.01 vs. control, ~~P < 0.01 vs. PISE, ▲▲P < 0.01 vs. HC-067047. d–f PISE-induced increases in IL-1β (d), TNF-α (e) and IL-6 (f) protein levels were markedly blocked by HC-067047. &&P < 0.01 vs. control, ~~P < 0.01 vs. PISE
Fig. 4 TRPV4 antagonist decreases NLRP3 inflammasome expression and proinflammatory cytokine production post-PISE. a–c Increased hippocampal protein levels of NLRP3 (a), ASC (b) and caspase-1 (c) post-PISE were markedly attenuated by HC-067047. &&P < 0.01 vs. control, ~~P < 0.01 vs. PISE, ▲▲P < 0.01 vs. HC-067047. d–f PISE-induced increases in IL-1β (d), TNF-α (e) and IL-6 (f) protein levels were markedly blocked by HC-067047. &&P < 0.01 vs. control, ~~P < 0.01 vs. PISECC BY · PubMed Central
Fig. 5 Possible mechanisms underlying the involvement of TRPV4 in neuronal injury in TLE. Activation of TRPV4 leads to microglial cell and astroycte activation, and the increase of NLRP3 inflammasome expression to produce more proinflammatory cytokines, which is involved in the neuronal injury in TLE. Blocking TRPV4 may attenuate neuronal injury post SE through inhibiting immuno-inflammatory response
Fig. 5 Possible mechanisms underlying the involvement of TRPV4 in neuronal injury in TLE. Activation of TRPV4 leads to microglial cell and astroycte activation, and the increase of NLRP3 inflammasome expression to produce more proinflammatory cytokines, which is involved in the neuronal injury in TLE. Blocking TRPV4 may attenuate neuronal injury post SE through inhibiting immuno-inflammatory responseCC BY · PubMed Central

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  1. Garcia-Elias, A. et al. The TRPV4 channel. Handb. Exp. Pharmacol. 222, 293–319 (2014). · DOI
  2. Scheraga, R. G., Southern, B. D., Grove, L. M. & Olman, M. A. The role of transient receptor potential vanilloid 4 in pulmonary inflammatory diseases. Front. Immunol. 8, 503 (2017). · DOI
  3. Jie, P. et al. Activation of transient receptor potential vanilloid 4 is involved in neuronal injury in middle cerebral artery occlusion in mice. Mol. Neurobiol. 53, 8–17 (2016). · DOI
  4. Bai, J. Z. & Lipski, J. Involvement of TRPV4 channels in Aβ(40)-induced hippocampal cell death and astrocytic Ca(2+) signalling. Neurotoxicology 41, 64–72 (2014). · DOI
  5. Yin, J. et al. Role of transient receptor potential vanilloid 4 in neutrophil activation and acute lung injury. Am. J. Respir. Cell Mol. Biol. 54, 370–383 (2016). · DOI
  6. Walter, B. A. et al. Reduced tissue osmolarity increases TRPV4 expression and pro-inflammatory cytokines in intervertebral disc cells. Eur. Cell. Mater. 32, 123–136 (2016). · DOI
  7. White, J. P. et al. TRPV4: molecular conductor of a diverse orchestra. Physiol. Rev. 96, 911–973 (2016). · DOI · Paper page
  8. Shi, M. et al. Glial cell-expressed mechanosensitive channel TRPV4 mediates infrasound-induced neuronal impairment. Acta Neuropathol. 126, 725–739 (2013). · DOI
  9. Farrell, J. S., Wolff, M. D. & Teskey, G. C. Neurodegeneration and Pathology in Epilepsy: clinical and basic perspectives. Adv. Neurobiol. 15, 317–334 (2017). · DOI
  10. Pitkänen, A. et al. Progression of neuronal damage after status epilepticus and during spontaneous seizures in a rat model of temporal lobe epilepsy. Prog. Brain. Res. 135, 67–83 (2002). · DOI
  11. Vezzani, A., French, J., Bartfai, T. & Baram, T. Z. The role of inflammation in epilepsy. Nat. Rev. Neurol. 7, 31–40 (2011). · DOI · Paper page
  12. Aronica, E. & Crino, P. B. Inflammation in epilepsy: clinical observations. Epilepsia 52, 26–32 (2011). · DOI · Paper page
  13. Hunt, R. F., Hortopan, G. A., Gillespie, A. & Baraban, S. C. A novel zebrafish model of hyperthermia-induced seizures reveals a role for TRPV4 channels and NMDA-type glutamate receptors. Exp. Neurol. 237, 199–206 (2012). · DOI
  14. Wu, B. et al. Ac-YVAD-CMK decreases blood-brain barrier degradation by inhibiting caspase-1 activation of interleukin-1β in intracerebral hemorrhage mouse model. Transl. Stroke Res. 1, 57–64 (2010). · DOI
  15. Shakeel, S., Rehman, M. U., Tabassum, N., Amin, U. & Mir, M. U. R. Effect of naringenin (a naturally occurring flavanone) against pilocarpine-induced status epilepticus and oxidative stress in Mice. Pharmacogn. Mag. 13, S154–S160 (2017). · DOI
  16. Racine, R. J. Modification of seizure activity by electrical stimulation: II. Motor seizure. Electroenceph. Clin. Neurophysiol. 32, 281–294 (1972). · DOI
  17. Hong, J. et al. Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons. Cell Death Dis. 6, e1832 (2015). · DOI
  18. Bauernfeind, F. et al. Inflammasomes: current understanding and open questions. Cell. Mol. Life Sci. 68, 765–783 (2011). · DOI
  19. Shao, B. Z., Cao, Q. & Liu, C. Targeting NLRP3 inflammasome in the treatment of CNS diseases. Front. Mol. Neurosci. 11, 320 (2018). · DOI
  20. Xiong, T. et al. The progressive changes of filamentous actin cytoskeleton in the hippocampal neurons after pilocarpine-induced status epilepticus. Epilepsy Res. 118, 55–67 (2015). · DOI
  21. Meng, X. F. et al. Inhibition of the NLRP3 inflammasome provides neuroprotection in rats following amygdala kindling-induced status epilepticus. J. Neuroinflammation. 11, 212 (2014). · DOI
  22. Shen, J. et al. TRPV4 channels stimulate Ca-induced Ca release in mouse neurons and trigger endoplasmic reticulum stress after intracerebral hemorrhage. Brain Res. Bull. 146, 143–152 (2019). · DOI
  23. Zhao, H. et al. TRPV4 blockade preserves the blood-brain barrier by inhibiting stress fiber formation in a rat model of intracerebral hemorrhage. Front. Mol. Neurosci. 11, 97 (2018). · DOI
  24. Lu, K. T., Huang, T. C., Tsai, Y. H. & Yang, Y. L. Transient receptor potential vanilloid type 4 channels mediate Na-K-Cl-co-transporter-induced brain edema after traumatic brain injury. J. Neurochem. 140, 718–727 (2017). · DOI
  25. Li, L. et al. Transient receptor potential vanilloid 4 mediates hypotonicity-induced enhancement of synaptic transmission in hippocampal slices. CNS Neurosci. Ther. 19, 854–862 (2013). · DOI
  26. Li, L. et al. Activation of transient receptor potential vanilloid 4 increases NMDA-activated current in hippocampal pyramidal neurons. Front. Cell. Neurosci. 7, 17 (2013).
  27. Shibasaki, K., Ikenaka, K., Tamalu, F., Tominaga, M. & Ishizaki, Y. A novel subtype of astrocytes expressing TRPV4 (transient receptor potential vanilloid 4) regulates neuronal excitability via release of gliotransmitters. J. Biol. Chem. 289, 14470–14480 (2014). · DOI · Paper page
  28. Jie, P. et al. Activation of transient receptor potential vanilloid 4 induces apoptosis in hippocampus through downregulating PI3K/Akt and upregulating p38 MAPK signaling pathways. Cell Death Dis. 6, e1775 (2015). · DOI
  29. Jie, P. et al. Blockage of transient receptor potential vanilloid 4 inhibits brain edema in middle cerebral artery occlusion mice. Front. Cell. Neurosci. 9, 141 (2015). · DOI
  30. Chen, C. K. et al. TRPV4 activation contributes functional recovery from ischemic stroke via angiogenesis and neurogenesis. Mol. Neurobiol. 55, 4127–4135 (2018).
  31. Rajasekhar, P., Poole, D. P. & Veldhuis, N. A. Role of Nonneuronal TRPV4 signaling in inflammatory processes. Adv. Pharmacol. 79, 117–139 (2017). · DOI
  32. Liu, M. et al. TRPV4 inhibition improved myelination and reduced glia reactivity and inflammation in a cuprizone-induced mouse model of demyelination. Front. Cell. Neurosci. 12, 392 (2018). · DOI
  33. Konno, M. et al. Stimulation of transient receptor potential vanilloid 4 channel suppresses abnormal activation of microglia induced by lipopolysaccharide. Glia 60, 761–770 (2012). · DOI
  34. Latz, E. The inflammasomes: mechanisms of activation and function. Curr. Opin. Immunol. 22, 28–33 (2010). · DOI
  35. Jin, C. & Flavell, R. A. Molecular mechanism of NLRP3 inflammasome activation. J. Clin. Immunol. 30, 628–631 (2010). · DOI · Paper page
  36. Zhong, Z. et al. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat. Commun. 4, 1611 (2013). · DOI
  37. Yao, H. et al. Inhibition of lanthanide nanocrystal-induced inflammasome activation in macrophages by a surface coating peptide through abrogation of ROS production and TRPM2-mediated Ca(2+) influx. Biomaterials. 108, 143–156 (2016). · DOI
  38. Hong, Z. et al. Enhanced oxidative stress is responsible for TRPV4-induced neurotoxicity. Front. Cell. Neurosci. 10, 232 (2016).
  39. Chen, L., Liu, C. & Liu, L. The modulation of voltage-gated potassium channels by anisotonicity in trigeminal ganglion neurons. Neuroscience 154, 482–495 (2008). · DOI
  40. Chen, X. et al. Increased expression of transient receptor potential vanilloid 4 in cortical lesions of patients with focal cortical dysplasia. CNS Neurosci. Ther. 22, 280–290 (2016). · DOI

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Metadata

Authors
Wang, Z., Zhou, L., An, D., Xu, W., Wu, C., Sha, S., Li, Y., Zhu, Y., Chen, A., Du, Y., Chen, L., & Chen, L.
Affiliations
  • Nanjing Medical University (CN)
  • Nanjing Children's Hospital (CN)
  • Wuhan Union Hospital (CN)
Corresponding author
  • Chen, Lei
  • Chen, Ling
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2019-05-16
Volume
10
Issue
6
Pages
386-386
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-019-1612-3
PMC
PMC6522539
OpenAlex
W2946016906
Cited by
149
References
3
Citations by year
2026: 12 · 2025: 15 · 2024: 31 · 2023: 25 · 2022: 29 · 2021: 17 · 2020: 17 · 2019: 2
FWCI
12.87
Type
journal article
Language
en
Update notices
correction (2019-06-21)
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Natural Science Foundation of China (81571270, 31571168, 81770328)
  • 13th Talents Project of Jiangsu Province (JY-049) to Lei Chen
Topics
  • Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
TRPV4, temporal lobe epilepsy, neuroinflammation, neuronal cell death, NLRP3 inflammasome, caspase-1, inflammatory cytokines, microglial activation, astrocyte activation, pilocarpine-induced status epilepticus, GSK1016790A, HC-067047, IL-1β, TNF-α, interleukin-6, neuroprotection, hippocampus, Ac-YVAD-cmk
MeSH terms
Animals, Astrocytes, Epilepsy, Temporal Lobe, Inflammation, Leucine, Male, Mice, Inbred ICR, Morpholines, Neurons, Pilocarpine, Pyrroles, Status Epilepticus, Sulfonamides, Microglia, TRPV Cation Channels, Mice, Inflammasomes

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