Gain of function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1b production. This cytokine is activated simultaneously with IL-18 by an intracellular protein complex known as the inflammasome, however IL-18 has not yet been implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified a disease in mice during which this occurs, due to inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when inflammasome components ASC, Caspase-1 or IL-18 are 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. Finally, small molecule inhibition of actin polymerization can remove potential danger signals from the system, and prevent monocyte IL-18 production. Previously, microbial perturbation of actin polymerization was shown to activate the inflammasome, so our data now extends this guard hypothesis to host regulated actin dependent processes and autoinflammatory disease.