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Originally published In Press as doi:10.1167/iovs.07-1355 on March 24, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:3004-3017.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-1355
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Contribution of TRPV1 to Microglia-Derived IL-6 and NF{kappa}B Translocation with Elevated Hydrostatic Pressure

Rebecca M. Sappington and David J. Calkins

From the Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee.

PURPOSE. The authors investigated the contributions of the transient receptor potential vanilloid-1 receptor (TRPV1) and Ca2+ to microglial IL-6 and nuclear factor kappa B (NF{kappa}B) translocation with elevated hydrostatic pressure.

METHODS. The authors first examined IL-6 colocalization with the microglia marker Iba-1 in the DBA/2 mouse model of glaucoma to establish relevance. They isolated microglia from rat retina and maintained them at ambient or elevated (+70 mm Hg) hydrostatic pressure in vitro and used ELISA and immunocytochemistry to measure changes in the IL-6 concentration and NF{kappa}B translocation induced by the Ca2+ chelator EGTA, the broad-spectrum Ca2+ channel inhibitor ruthenium red, and the TRPV1 antagonist iodo-resiniferatoxin (I-RTX). They applied the Ca2+ dye Fluo-4 AM to measure changes in intracellular Ca2+ at elevated pressure induced by I-RTX and confirmed TRPV1 expression in microglia using PCR and immunocytochemistry.

RESULTS. In DBA/2 retina, elevated intraocular pressure increased microglial IL-6 in the ganglion cell layer. Elevated hydrostatic pressure (24 hours) increased microglial IL-6 release, cytosolic NF{kappa}B, and NF{kappa}B translocation in vitro. These effects were reduced substantially by EGTA and ruthenium red. Antagonism of TRPV1 in microglia partially inhibited pressure-induced increases in IL-6 release and NF{kappa}B translocation. Brief elevated pressure (1 hour) induced a significant increase in microglial intracellular Ca2+ that was partially attenuated by TRPV1 antagonism.

CONCLUSIONS. Elevated pressure induces an influx of extracellular Ca2+ in retinal microglia that precedes the activation of NF{kappa}B and the subsequent production and release of IL-6 and is at least partially dependent on the activation of TRPV1 and other ruthenium red-sensitive channels.






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