A role for transient receptor potential vanilloid 4 in tonicity-induced neurogenic inflammation
Article first published online: 5 FEB 2010
Journal compilation © 2010 The British Pharmacological Society. No claim to original US government works
British Journal of Pharmacology
Special Issue: Themed Section: Molecular Pharmacology of G Protein-Coupled Receptors: Guest Editor: RJ Summers
Volume 159, Issue 5, pages 1161–1173, March 2010
How to Cite
Vergnolle, N., Cenac, N., Altier, C., Cellars, L., Chapman, K., Zamponi, G., Materazzi, S., Nassini, R., Liedtke, W., Cattaruzza, F., Grady, E., Geppetti, P. and Bunnett, N. (2010), A role for transient receptor potential vanilloid 4 in tonicity-induced neurogenic inflammation. British Journal of Pharmacology, 159: 1161–1173. doi: 10.1111/j.1476-5381.2009.00590.x
- Issue published online: 10 MAR 2010
- Article first published online: 5 FEB 2010
- Received 28 July 2009; revised September 2009; accepted 16 October 2009
- Transient receptor potential vanilloid 4;
- neurogenic inflammation;
- substance P;
- calcitonin gene-related peptide
Background and purpose: Changes in extracellular fluid osmolarity, which occur after tissue damage and disease, cause inflammation and maintain chronic inflammatory states by unknown mechanisms. Here, we investigated whether the osmosensitive channel, transient receptor potential vanilloid 4 (TRPV4), mediates inflammation to hypotonic stimuli by a neurogenic mechanism.
Experimental approach: TRPV4 was localized in dorsal root ganglia (DRG) by immunofluorescence. The effects of TRPV4 agonists on release of pro-inflammatory neuropeptides from peripheral tissues and on inflammation were examined.
Key results: Immunoreactive TRPV4 was detected in DRG neurones innervating the mouse hindpaw, where it was co-expressed in some neurones with CGRP and substance P, mediators of neurogenic inflammation. Hypotonic solutions and 4α-phorbol 12,13-didecanoate, which activate TRPV4, stimulated neuropeptide release in urinary bladder and airways, sites of neurogenic inflammation. Intraplantar injection of hypotonic solutions and 4α-phorbol 12,13-didecanoate caused oedema and granulocyte recruitment. These effects were inhibited by a desensitizing dose of the neurotoxin capsaicin, antagonists of CGRP and substance P receptors, and TRPV4 gene knockdown or deletion. In contrast, antagonism of neuropeptide receptors and disruption of TRPV4 did not prevent this oedema. TRPV4 gene knockdown or deletion also markedly reduced oedema and granulocyte infiltration induced by intraplantar injection of formalin.
Conclusions and implications: Activation of TRPV4 stimulates neuropeptide release from afferent nerves and induces neurogenic inflammation. This mechanism may mediate the generation and maintenance of inflammation after injury and during diseases, in which there are changes in extracellular osmolarity. Antagonism of TRPV4 may offer a therapeutic approach for inflammatory hyperalgesia and chronic inflammation.