Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1beta

Man Lyang Kim, Jae Jin Chae, Yong Hwan Park, Dominic De Nardo, Roslynn A Stirzaker, Hyun-Ja Ko, Hazel Tye, Louise Cengia, Ladina Di Rago, Donald Metcalf, Andrew W Roberts, Daniel L Kastner, Andrew M Lew, Dena Lyras, Benjamin T. Kile, Ben A Croker, Seth L Masters

Research output: Contribution to journalArticleResearchpeer-review

82 Citations (Scopus)

Abstract

Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1beta production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1beta, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease.
Original languageEnglish
Pages (from-to)927-938
Number of pages12
JournalJournal of Experimental Medicine
Volume212
Issue number6
DOIs
Publication statusPublished - 2015

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