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Jessica Carter, Shauntelle Byfield, Jay Oh, Judee Grace Nemeño, Richard D Dix; IL-1R1 and IL-18 are Essential for Development of Experimental Murine Cytomegalovirus (MCMV) Retinitis in Mice with Retrovirus-Induced Immunosuppression (MAIDS). Invest. Ophthalmol. Vis. Sci. 2019;60(9):4614.
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Interleukin-1β (IL-1β) and IL-18 are produced as inactive precursors that are cleaved by caspase-1 following inflammasome activation and released from host cells during pyroptotic cell death. We have shown previously that pyroptosis-associated molecules are stimulated within MCMV-infected eyes during the progression of retinitis in mice with MAIDS and that NLRP3 and NLRP1b inflammasomes are essential to the development of MCMV retinitis. To determine the mechanism(s) involved in inflammasome-dependent MCMV retinitis, we tested the hypothesis that the inflammatory-mediated IL-1 type 1 receptor (IL-1R1) and/or IL-18 are required for the pathogenesis of MAIDS-related MCMV retinitis.
Eyes of groups (n = 5 – 9) of MAIDS mice deficient in IL-1R1 (MAIDS IL-1R1 KO mice), MAIDS mice deficient in IL-18 (MAIDS IL-18 KO mice), and wildtype C57BL/6 mice with MAIDS (MAIDS WT mice) were injected subretinally with MCMV. MCMV-infected eyes were harvested 10 days later and assessed for intraocular MCMV amounts, frequency of full-thickness retinal necrosis, and pyroptosis-associated protein expression.
Despite no difference in intraocular MCMV amounts, none (0%) of MCMV-infected eyes of MAIDS IL-1R1 KO mice and MAIDS IL-18 KO mice developed full-thickness retinal necrosis as observed in 75% and 86% of MCMV-infected eyes of MAIDS WT mice. Histopathologic analysis of MCMV-infected eyes of MAIDS IL-1R1 KO mice and MAIDS IL-18 KO mice revealed proliferation of inclusion-bearing RPE cells, but sparing of the neurosensory retina. Western blot analysis showed expected NLRP3 inflammasome, caspase-1, and caspase-11 protein expression in MCMV-infected eyes of MAIDS IL-1R1 KO mice and MAIDS IL-18 KO mice as seen in MCMV-infected eyes of MAIDS WT mice. Importantly, cleaved gasdermin D (GSDMD), an indicator of pyroptosis, was observed in MCMV-infected eyes of MAIDS WT mice and MAIDS IL-18 KO mice, but not in MCMV-infected eyes of MAIDS IL-R1 KO mice.
Reduced frequency of full-thickness retinal necrosis in MCMV-infected eyes of MAIDS IL-1R1 KO mice and MAIDS IL-18 KO mice supports a role for IL-1R1 and IL-18 in the pathogenesis of MAIDS-related MCMV retinitis. Nonetheless, the unexpected finding that GSDMD is uncleaved in MCMV-infected eyes of MAIDS IL-1R1 KO mice suggests that pyroptosis is not operating in these eyes.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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