Role of Retinoid X Receptors on survival and modulation of inflammatory response, in retinal pigment epithelium cells upon different stressors, such as H2O2 and viral infection.

AYALA PEÑA, V.B.; ARMIENTO, N. ; SCOLARO, L. ; GERMAN, O.L.

Mar del plata, Buenos aires, Argentina.

Congreso; SAIC-SAI-SAFE 2016; 2016

Age-related macular degeneration (AMD) is the main pathology leading to blindness in adults and has currently no cure or effective treatment. Retinal pigment epithelial (RPE) cells have immunomodulatory properties and their degeneration contributes in AMD development. Oxidative stress is one of the events involved in the pathogenesis of this disease, and herpes simplex virus type 1 (HSV-1) infection is currently proposed as a probable risk factor.We previously demonstrated that RXR activation with HX630 protects RPE (D407) cells from H2O2-induced apoptosis. HX630 prevents p65NFκB nuclear translocation (which is also crucial for triggering inflammation) and increases PPARγ mRNA levels. LG100754 (a RXR homodimers antagonist and a RXR agonist that could activate RXR/PPARγ) also had a protective effect. In this work using a PPARγ specific agonist and their antagonist, we reproduced the protective effect of RXR activation against oxidative damage, determined by MTT assay and fluorescence microscopy. We observed by qRT-PCR that RXR activation decreased IL-6 (a pro-inflammatory cytokine) and increased IL-10 and TGFβ (anti-inflammatory cytokines) mRNA levels significantly. It is known that HSV-1 blocks the synthesis of RXRα in macrophage promoting the host antiviral response. In HSV-1 infected D407 cells, PPARγ mRNA level but not RXRα was significantly decreased compared to mock infected cultures, even under LG100754 treatment. Using fluorescence microscopy, p65NFkB protein level was increased in the whole cell; however, the nuclear/total p65NFkB fluorescence proportion in infected cells was decreased compared to the mock infected cells, even under LG100754 treatment. Furthermore, the infection blocked the synthesis of TGFβ mRNA and the RXR agonist could not improve it. As a whole, our results suggest that RXR/PPARγ heterodimers would be a central signaling in survival and inflammatory response upon H2O2 in RPE cells, which could be regulated by HSV-1 infection.