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Valery I Shestopalov, Galina Dvoriantchikova, Sarah Kurtenbach, Ashlyn Reiser, Zhanna kokzhekbaeva, Alexander Tuzhikov; Ganglion cell loss in ocular and glaucoma is facilitated by the Panx1-regulated inflammasome. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2247.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal ganglion cell (RGC) loss is characteristic to retinal ischemia and optic nerve injuries of various etiologies, including glaucoma, autoimmune optic neuritis and ischemic optic neuropathy. The neurotoxicity in these pathologies is commonly associated with activation of pro-inflammatory pathways linked to activation of NLRP1/3 inflammasome complex that controls production of the IL-1b/IL-18 cytokines. This study tested a hypothesis stating that pathological induction of NALP1/3 is the key event leading to the RGC death.
We utilized two alternative models of RGC death: 1) retinal ischemia-reperfusion (IR) and 2) microbead-indiced glaucoma. Mouse lines lacking pannexin1 (Panx1), caspase-1 (Casp1) and caspase-11 (Casp11) were used to examine inflammasome activation and toxicity pathways. This was sufficient to protect up to 90-100% of RGC in both animal models. Probenecid treatment was used for pharmacological blockade of Panx1 channels.
Ischemia-induced levels of inflammasome convertases caspase-1 and caspase-11, as well as mature IL-1b were significantly decreased in the retinas of Casp1-null, Panx1-null and WT probenecid-treated mice relative to IR-exposed control retinas. Our disease model data show that the ablation or blockade of Panx1 and Casp1, but not Casp11 was required to significantly inhibit inflammasome activation. This was sufficient to protect up to 90-98% of RGC in both animal models, a significant increase relative to that in wild type (WT) retinas. The same degree of protection was observed in mice treated with a Panx1 inhibitor probenecid.
Our results indicate that Panx1–regulated NLRP1/3 inflammasome and Casp1 activation is the key pathway contributing to RGC loss IOP-induced glaucomatous and ischemic optic nerve injury. Targeting Panx1, Casp1 and/or inflammasome represent a feasible neuroprotective strategy in retinal and optic nerve pathologies with significant ischemic and inflammatory components.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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