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Jiangyuan Gao, Sijia Cao, Aikun Wang, Jing Z Cui, Patrick L. McGeer, Joanne A Matsubara; XIAP Involvement in RPE Inflammasome and Cell Death Regulation. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6542. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Age-related macular degeneration (AMD) is a neurodegenerative disease that features cell death in retinal pigment epithelium (RPE) and photoreceptor. X-linked inhibitor of apoptosis (XIAP), an anti-apoptotic protein, used in models of retinal degeneration, has recently been implicated in regulating inflammasome activity in non-ocular, immune cells. The purpose of this study is to test the merit of XIAP being a dual regulator of inflammasome activation and cell death.
Adult Long-Evans rats were divided into three treatment groups. The first group used a complement cascade inhibitor, aurin tricarboxylic acid complex (ATAC). Following our published protocols, naive rats received ATAC in drinking water for 40 days, or drinking water alone, and then sacrificed. The second group used an NF-κB inhibitor, vinpocetine. All rats first received an intraocular injection of Aβ, a component of drusen, followed by either a daily I.P. injection of vinpocetine for 3 consecutive days, or an I.P. injection of vehicle (DMSO). In the third group, each rat received one intraocular injection of either Aβ or reverse Aβ every 4 days, for 3 times.
Our earlier work demonstrated that inhibition of the NF-κB pathway by vinpocetine reduced Aβ induced caspase-1 cleavage in the eye. We also reported that by suppressing the end product of complement activation, membrane attack complex with ATAC, caspase-1 cleavage is diminished in the eye as well. Here, we showed in the same experimental scenarios, XIAP protein level is lowered by ATAC, but not by vinpocetine, suggesting XIAP might associate with the assembly of NLRP3 inflammasome. Moreover, compared to the control animals, the multiple Aβ treatment group showed a significant decrease in both mRNA and protein levels of XIAP, with a concomitant increase in RIP1, ZO-1, and RPE65 mRNAs, indicating a decline in RPE homeostasis.
Despite the fact that XIAP is a classic anti-apoptotic factor, little is known about its role in regulating inflammatory responses. This study provides proof-of-evidence that XIAP is a potential novel candidate for modulating (suppressing) caspase-1 dependent inflammasome activation. Given that chronic inflammation and RPE apoptosis are features in the pathogenesis of AMD, further investigation to fully characterize XIAP’s dual role as an inhibitor of caspase-3 dependent apoptosis and caspase-1 dependent inflammasome activation seems warranted.
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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