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Alaina Reagan, Michael H Elliott; CAVEOLIN-1 MODULATES RETINAL DAMAGE RESPONSE FOLLOWING ACUTE ISCHEMIA REPERFUSION. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4959.
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© ARVO (1962-2015); The Authors (2016-present)
Caveolin-1, (Cav-1) the primary scaffolding protein of caveolae membrane domains, mediates Toll-like receptor signaling in the retina. We have recently shown that Cav-1 deficiency blunts TLR4 activation to an acute inflammatory stimulus. Retinal ischemia/reperfusion (I/R) injury induced by acute ocular hypertension also activates TLR4. Given the association of CAV1/2 polymorphisms with glaucoma we hypothesized that Cav-1 might suppress retinal neuroinflammatory/neuroprotective responses to I/R injury to the inner retina.
To induce an elevated IOP, transient ischemia was induced in one eye of Cav-1 knockout (KO) and control mice by inserting a 33-gauge needle connected to a saline reservoir into the anterior chamber through the cornea. Intraocular pressure was raised to 100 mmHg for 50 minutes and then the needle was removed to allow for retinal reperfusion. Contralateral eyes were used as controls. Twenty-four hours after I/R insult, retinas were isolated to assess the production of the TLR4-activated cytokine, interleukin-6 (IL-6) by ELISA. Two weeks after I/R insult, retinal ganglion cell (RGC) numbers were assessed in whole mounts by immunohistochemical localization of Brn3a and βIII-tubulin.
I/R injury induced a dramatic increase in IL-6 protein levels in control retinas as others have reported. Importantly, injury-induced IL-6 levels were dramatically suppressed in Cav-1 KO animals. These results are consistent with our previous findings of blunted TLR4 signaling in response to retinal inflammatory insult. Because TLR4 activation in retinal I/R injury potentiates damage, we predicted that loss of Cav-1 might protect against RGC loss. RGC numbers were not different between genotypes in uninjured sham controls. However, following I/R injury we found significantly increased numbers of Brn3a-positive RGCs in Cav-1 KO retinas compared to controls (1611 ± 323 vs 872 ± 141 RGCs/mm2; KO vs control) suggesting that reduced TLR4 activation as a consequence of Cav-1 deficiency may be neuroprotective.
These data further support a modulatory role for Cav-1 in TLR4 signaling. Our results are consistent with the idea that Cav-1 ablation dampens TLR4 activation downstream cytokine production, and may promote neuronal survival in response to retinal injury.
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