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Mechanisms of NLRP3 Inflammasome Activation in CAPS Patients

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Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

Mutations in the inflammasome gene NLRP3, with consequent increase of IL-1β secretion, are responsible for a group of autoinflammatory syndromes collectively named Cryopyrin Associated Periodic Syndromes (CAPS). Despite the clear role of NLRP3 in orchestrating key pathways in innate immunity, such as the activation of IL-1β, the molecular mechanism(s) underlying inflammasome assembly remain largely unknown, both in healthy conditions and in CAPS. Redox-related reactions have been proposed to play a crucial role. However, the type of redox response involved as well as the relevant role of prooxidant and antioxidant events are matter of intense debate. Herein, we review the current knowledge of mechanisms leading to the activation of NLRP3 inflammasome in autoinflammatory diseases. In particular, we present a model illustrating how redox signalling controls wild-type and mutated NLRP3 inflammasome activation. Studying monocytes from patients carrying mutations in NLRP3 gene, we have identified a redox signature characterized by increased levels of Reactive Oxygen Species (ROS) and up-regulation of antioxidant systems. This altered redox state is implicated in the accelerated kinetics of IL-1β secretion observed in Toll-like Receptor stimulated CAPS monocytes. We propose that in CAPS patients the collusion between redox derangement and gain-of-function mutations of NLRP3 results in both increased and accelerated IL-1β secretion leading to severe clinical manifestations.

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Correspondence to Anna Rubartelli .

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Gattorno, M., Rubartelli, A. (2011). Mechanisms of NLRP3 Inflammasome Activation in CAPS Patients. In: Couillin, I., Pétrilli, V., Martinon, F. (eds) The Inflammasomes. Progress in Inflammation Research. Springer, Basel. https://doi.org/10.1007/978-3-0348-0148-5_12

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  • DOI: https://doi.org/10.1007/978-3-0348-0148-5_12

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