Complement-Mediated Activation of the NLRP3 Inflammasome and Its Inhibition by AAV-Mediated Delivery of CD59 in a Model of Uveitis

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Abstract

Uveitis is an inflammatory disorder of the eye responsible for approximately 10%–15% of blindness in the US. In this study, we examined the role of the complement membrane attack complex (MAC) and the NLRP3 inflammasome in the pathogenesis of experimental autoimmune uveitis (EAU) in normal and C9 −/− mice that are incapable of assembling the MAC. We discovered that the MAC and the NLRP3 inflammasome and associated production of IL-1β are elevated in EAU mice and that MAC may be involved in regulation of Th1 and Th17 cell differentiation. In contrast, MAC and the NLRP3 inflammasome were not elevated in C9 −/− mice. However, EAU-associated pathophysiology including retinal structure and function were not rescued in C9 −/− mice. Unexpectedly, AAV-mediated delivery of sCD59, an inhibitor of C9 incorporation into the MAC, successfully attenuated activation of the NLRP3 inflammasome and EAU pathology as well as MAC. Our studies provide an improved understanding of the role of the MAC and the NLRP3 inflammasome in EAU as well as suggest a novel approach for the treatment of uveitis. Uveitis is an inflammatory disorder of the eye. Kumar et al. describe complement membrane attack complex (MAC) mediated activation of the NLRP3 inflammasome that could be inhibited by AAV-mediated delivery of CD59 in a model of uveitis, providing proof of concept for a novel therapy.

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Kumar, B., Cashman, S. M., & Kumar-Singh, R. (2018). Complement-Mediated Activation of the NLRP3 Inflammasome and Its Inhibition by AAV-Mediated Delivery of CD59 in a Model of Uveitis. Molecular Therapy, 26(6), 1568–1580. https://doi.org/10.1016/j.ymthe.2018.03.012

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