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Aram Asatryan, Jorgelina Muriel Calandria, Nicolas G Bazan; NPD1 transcriptional activation of c-REL is essential to contain AIM2 and NOD-2 inflammasome formation in RPE cells. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):814.
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© ARVO (1962-2015); The Authors (2016-present)
The progression of age-related macular degeneration (AMD) is associated with aberrant inflammatory and immune responses. Drusen that accumulates between Bruch’s membrane and RPE cells can be “sensed” by the NLRP3 inflammasome, climaxing in the release of the pro-inflammatory cytokines IL-1β and IL-18. Previously, we have shown that a docosahexaenoic acid (DHA)-derived lipid mediator neuroprotectin D1 (NPD1), produced in response to oxidative stress, up-regulates the expression of BIRC3 through transcriptional activation of cREL: a member of the NFκB family (Calandria et al., Cell Death Diff, 2014, in press). We hypothesized that NPD1 regulates the expression of components of inflammasomes at the transcriptional level.
To define the mechanisms by which NPD1 modulates inflammasomes, we used retinal pigment epithelial (RPE) cells as an in vitro model. Inflammasomes have been shown to be formed following oxidative stress induction (Immun Letters, 147 (2012) 29-33). Cells were treated with 600µM H2O2 and 10ng/ml TNFα to induce oxidative stress and were rescued with 200nM NPD1 for 6 hours. Extracted RNA samples were analyzed using a custom-made Prime PCR Panel for human inflammasome. To understand the extent of the effect of NPD1 in inflammasome formation upon oxidative stress induction, we silenced both BIRC3 and cREL expression using siRNA and analyzed on the same PCR panel.
Oxidative stress triggered the expression of numerous major inflammasome components, including AIM2, NOD-2 and NLRC4. The expression of AIM-2 and NOD-2 was down-regulated three-fold in the presence of NPD1. Interestingly, NPD1 decreased the expression of inflammasome end product IL-1β 2.5-fold when compared with oxidative stress alone. Silencing of either BIRC3 or c-REL separately or concurrently abolishes the effect of NPD1.
Our results suggest that NPD1 inhibits inflammasome formation at the transcriptional level. Particularly of interest is the AIM2 inflammasome, which is linked to various autoimmune diseases. NOD-2 forms so-called “nodosomes” that result in the activation of pro-inflammatory NFκB. NOD2 is also involved in the activation of caspase-1 and IL-1β, however formation of this inflammasome requires the presence of NALP3. Overall, inflammasome modulation by NPD1 in the RPE cell might be central to events that sustain photoreceptors function.
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