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Hsin Chien, Emily L. Blalock, Lauren R. Bush, Christi I. Alston, Richard D. Dix; The Caspase-1-induced Pyroptotic Cell Death Pathway (Pyroptosis) Is Upregulated During Progression Of Experimental Murine Cytomegalovirus (MCMV) Retinitis in Mice With Retrovirus-induced Immunosuppression (MAIDS). Invest. Ophthalmol. Vis. Sci. 2012;53(14):6225.
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Pyroptosis, a cell death pathway different from apoptosis and necrosis, is triggered by active caspase-1 resulting in release of cellular contents that leads to inflammation. Secretion of interleukin-1β (IL-1β) and IL-18 coincide with pyroptosis-associated inflammation. Since our previous work suggested that TNF-α-induced apoptosis contributes minimally to onset and progression of retinal disease during MAIDS-related MCMV retinitis, we hypothesized that pyroptosis also contributes to retinal disease development during MAIDS.
Groups of C57BL/6 mice with MAIDS of 4-weeks (retinitis resistant) or 10-weeks (retinitis susceptible) duration were injected subretinally with MCMV or mock-injected (control). At days 3, 6, and 10 days postinfection, whole eyes were collected and subjected to real time RT-PCR assay, ELISA, or western blotting for quantification of caspase-1, IL-1β, and IL-18 mRNAs and proteins. Sections of whole eyes collected from all animals were also subjected to immunostaining for localization of active caspase-1 production.
When compared with mock-infected eyes, MCMV-infected eyes from MAIDS-10 mice exhibited a significant increase in caspase-1 (66-fold), IL-1β (786-fold), and IL-18 (19-fold) mRNA levels at day 6 postinfection prior to retinitis development, patterns similar to that for protein production. In contrast, MCMV-infected eyes from MAIDS-4 mice showed minimal increases or no detectable changes in caspase-1, IL-1β, and IL-18 mRNA and protein levels at day 6 postinfection. Caspase-1 protein was detectable in ganglion cell and photoreceptor layers of MCMV-infected eyes of MAIDS-10 mice, although some caspase-1-positive cells were double positive for F4/80, a macrophage marker.
Whereas caspase-1, IL-1β, and IL-18 mRNAs and proteins (all involved in the pyroptotic cell death pathway) were significantly upregulated in MCMV-infected eyes of MAIDS-10 mice during development of retinitis, these pyroptotic-associated molecules were relatively quiet in MCMV-infected eyes of MAIDS-4 mice resistant to development of retinitis. A source for caspase-1 production included infiltrating macrophages. We conclude that pyroptosis plays a role in the pathogenesis of MAIDS-related MCMV retinitis.
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