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Jing Z Cui, Tom Zhao, Jiangyuan Gao, Jenifer Van, Eleanor To, Aikun Wang, Sijia Cao, Patrick L McGeer, Joanne A Matsubara; Suppression of Membrane Attack Complex Reduces Inflammasome Activation in the Rodent Eye. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3776.
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The membrane attack complex (MAC) is a key player in the pathogenesis of age-related macular degeneration (AMD) and is a putative activator of the NLRP3 inflammasome. Aβ, a component of drusen, is also a candidate activator of the inflammasome. However, the interactions of MAC and Aβ are poorly understood. Since inflammasome activation may represent a key cellular pathway underlying age-related chronic inflammation in the eye, the purpose of this study is to identify the effects associated with MAC and inflammasome activation in the outer retina and to evaluate the therapeutic merits of MAC suppression.
Adult Long-Evans rats were divided into treatment and control groups. Treatment groups received oral aurin tricarboxylic acid complex (ATAC) in drinking water and control groups received drinking water alone (no ATAC). Groups were sacrificed at 7.5 or 11.5 months, after approximately 40 days of ATAC treatment. To study age-related changes of Aβ and MAC in outer retina, naive animals were sacrificed at 2.5, 7.5, and 11.5-months of age. Eye tissues underwent immunohistochemistry and western blot analysis for MAC, Aβ, NF-κB activation, as well as cleaved caspase-1, an indicator of inflammasome activation, and IL18, a mature product of inflammasome activation. Vitreal samples were collected and assessed by multiplex assays for secreted levels of IL18 and IL1β.
Immunohistochemistry and Western blot analysis demonstrated an age-dependent increase in MAC, Aβ and NF-κB activation in the outer retina. We then assessed the efficacy of ATAC on inflammasome activation. Systemic ATAC resulted in a prominent reduction in MAC formation in outer retina and a concomitant reduction in inflammasome activation measured by cleaved caspase-1 and secreted levels of IL18 and IL1β. Systemic ATAC did not affect NF-κB activation in RPE cells.
A naturally occurring, age-related build-up of MAC and Aβ was observed in rat outer retina, and is consistent with observations from postmortem human eyes. Systemic treatment with ATAC in rodents resulted in a prominent reduction of MAC deposition and a subsequent decrease in NLRP3 inflammasome activation. Given that MAC is a putative activation signal of the NLRP3 inflammasome, our results suggest that targeting MAC with ATAC may be a method to suppress NLRP3 inflammasome activation and thereby reduce levels of IL1β and IL18 in ocular tissues.
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