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Wedelolactone protects DNA-induced photoreceptor death
Kevin Harkin, Sofia Pavlou, Alan W Stitt, Heping Xu, Mei Chen;
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© ARVO (1962-2015); The Authors (2016-present)
<p>Photoreceptor cell death attributes to vision loss in multiple retinal disorders. Oxidative stress damages mitochondria resulting in the release of mtDNA into the cytosol, which can activate the Absent in Melanoma 2 (Aim2) inflammasome pathway. Downstream signaling of this inflammasome can trigger Caspase 4 (Casp4) maturation, inflammatory cytokine (i.e. Il18, Il1β) production and subsequent pyroptosis. In this study, we tested whether Wedelolactone (WD), a novel Casp4 inhibitor, can attenuate DNA-induced photoreceptor cell death by inhibiting the Aim2 inflammasome signaling pathway.</p>
<p>661w photoreceptor cells were transfected with poly(dA:dT) (5 µg/ml) to induce cell death which was examined using the YO-PRO-1 assay. The expression of Aim2, Casp4 and Il18 was analyzed by qRT-PCR (for mRNA expression), immunohistochemistry (IHC) and ELISA (for protein expression). The effects of WD (50 µM) on these readouts was evaluated.</p>
<p>Poly(dA:dT) induced photoreceptor death after 8 hours and was associated with the upregulation of Aim2, Casp4 and Il18 at the mRNA level (p<0.05). WD significantly attenuated poly(dA:dT)-induced cell death (p<0.05), and reduced poly(dA:dT)-mediated upregulation of Aim2, Casp4 and Il18 (p<0.05). IHC showed that poly(dA:dT) treatment increased the expression of Casp4, but not Aim2, and WD blunted poly(dA:dT)-mediated Casp4 expression. The concentration of Il18 in the supernatant was significantly increased in poly(dA:dT) treated cells (p<0.001), with WD suppressing Il18 production in both control (p<0.05) and treatment (p<0.001) groups.</p>
<p>Poly(dA:dT) induces Aim2 inflammasome activation and cell death in photoreceptor cells. WD can attenuate poly(dA:dT)-induced photoreceptor death by suppressing Aim2 inflammasome signaling. WD may be useful as a therapeutic agent in attenuating photoreceptor cell death and subsequent vision loss.</p>
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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