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Richard D Dix, Christine Iris Alston, Hsin Chien; Both canonical and non-canonical inflammasome systems may operate during development of murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunodeficiency (MAIDS). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1867.
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NLR proteins are innate immune sensors that can form large complexes called canonical inflammasomes that activate caspase-1 and induce production of active IL-1beta and IL-18 that can lead to pyroptosis, an inflammatory cell death program. A second inflammatory caspase, caspase-11, may also mediate pyroptosis through a non-canonical inflammasome system. We therefore performed studies to test the hypothesis that key molecules required for both canonical and non-canonical inflammasome systems are stimulated during development of experimental MCMV retinitis in mice with 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 postinfection, whole eyes were collected and subjected to real time RT-PCR and/or western blot assays for quantification of AIM2, NLRP1b, NLRP3, NLRC4, caspase-1, IL-1beta, and caspase-11 mRNAs and/or proteins, respectively.
When compared with mock-infected eyes, MCMV-infected eyes from MAIDS-10 mice exhibited a significant increase in AIM2, NLRP1b, NLRP3, and NLRC4 mRNAs and caspase-1, IL-1beta and caspase-11 proteins at day 6 postinfection prior to retinitis development. In contrast, MCMV-infected eyes from MAIDS-4 mice showed minimal or no detectable changes in production of these molecules at day 6 postinfection.
Key molecules associated with canonical inflammasomes as well as non-canonical inflammasomes that are involved in the development of pyroptosis were significantly stimulated within MCMV-infected eyes of MAIDS-10 mice that develop retinitis, but were only minimally stimulated or not detected within MCMV-infected eyes of MAIDS-4 mice that do not develop retinitis. These findings suggest that both canonical and non-canonical inflammasome systems may operate during development of MCMV retinitis in mice with MAIDS and lead to pyroptosis, another cell death mechanism by which retinal tissue destruction may occur during MAIDS-related MCMV retinitis.<br />
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