Journal article
Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β
ML Kim, JJ Chae, YH Park, D De Nardo, RA Stirzaker, HJ Ko, H Tye, L Cengia, L DiRago, D Metcalf, AW Roberts, DL Kastner, AM Lew, D Lyras, BT Kile, BA Croker, SL Masters
Journal of Experimental Medicine | Published : 2015
DOI: 10.1084/jem.20142384
Abstract
Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1β 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-1β, resulting from an inactivating mutation of the actindepolymerizing 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 ..
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Awarded by National Institute of Allergy and Infectious Diseases
Funding Acknowledgements
This work was supported by project grants (1008131 and 1043414), program grants (1016647 and 1037321), fellowships (to B.T. Kile, B.A. Croker, A.M. Lew, and S.L. Masters), a National Institutes of Health grant (1R56AI103352-01A1; to B.A. Croker), and an Independent Research Institutes Infrastructure Support Scheme grant (361646) from the National Health and Medical Research Council; fellowships from the Victorian Endowment for Science Knowledge and Innovation (to S.L. Masters), the Australian Research Council (to B.A. Croker and B.T. Kile), the Sylvia and Charles Viertel Charitable Foundation (to B.T. Kile), and the Cancer Council of Victoria (to D. Metcalf); the Australian Cancer Research Foundation, the Australian Phenomics Network, and a Victorian State Government Operational Infrastructure Support grant.