Abstract
Purpose :
Pyroptosis is a cell death pathway whose potential contributions to retinal disease remain unexplored. We have shown previously that key pyroptosis-related molecules caspase-1, interleukin-1β (IL-1β), and IL-18 mRNAs are stimulated within MCMV-infected eyes during the progression of retinitis in mice with MAIDS [J Virol, 2012]. To determine the mechanism(s) by which MCMV might stimulate pyroptosis, we performed a series of in vivo studies to test the hypothesis that mRNA for gasdermin D (GSDMD), a recently discovered molecule that is critical for release of IL-1β during pyroptosis, is stimulated during the pathogenesis of MAIDS-related MCMV retinitis.
Methods :
Groups of retinitis-sensitive mice with MAIDS (n = 3 – 5) were injected subretinally with MCMV (left eyes) or maintenance medium only (right eyes). MCMV-infected and control eyes were harvested at 6 and 10 days after subretinal injection and assessed for GSDMD mRNA by quantitative real-time RT-PCR assay. Results: As expected, MCMV-infected eyes of retinitis-susceptible mice with MAIDS showed marked stimulation of IL-1β mRNA production when compared with uninfected control eyes that peaked at day 6 after subretinal MCMV inoculation. In comparison, MCMV-infected eyes of retinitis-susceptible mice with MAIDS showed a modest yet significant stimulation of GSDMD mRNA at days 6 and 10 after subretinal MCMV inoculation.
Results :
As expected, MCMV-infected eyes of retinitis-susceptible mice with MAIDS showed marked stimulation of IL-1β mRNA production when compared with uninfected control eyes that peaked at day 6 after subretinal MCMV inoculation. In comparison, MCMV-infected eyes of retinitis-susceptible mice with MAIDS showed a modest yet significant stimulation of GSDMD mRNA at days 6 and 10 after subretinal MCMV inoculation.
Conclusions :
That MCMV-infected eyes of retinitis-sensitive mice with MAIDS showed stimulation of GSDMD mRNA production concomitant with stimulation of IL-1β mRNA production further supports a role for pyroptosis in the pathogenesis of MAIDS-related MCMV retinitis and agrees with recent findings that GSDMD production is related to release of the pyroptosis-related molecule IL-1β. Studies are underway to determine if IL-1β mRNA stimulation is dependent or independent of caspase-1 and/or caspase-11.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.