Journal article

The Pyroptotic Cell Death Effector Gasdermin D Is Activated by Gout-Associated Uric Acid Crystals but Is Dispensable for Cell Death and IL-1 beta Release

Maryam Rashidi, Daniel S Simpson, Anne Hempel, Daniel Frank, Emma Petrie, Angelina Vince, Rebecca Feltham, Jane Murphy, Simon M Chatfield, Guy S Salvesen, James M Murphy, Ian P Wicks, James E Vince

The Journal of Immunology | AMER ASSOC IMMUNOLOGISTS | Published : 2019

Abstract

The pyroptotic cell death effector gasdermin D (GSDMD) is required for murine models of hereditary inflammasome-driven, IL-1β-dependent, autoinflammatory disease, making it an attractive therapeutic target. However, the importance of GSDMD for more common conditions mediated by pathological IL-1β activation, such as gout, remain unclear. In this study, we address whether GSDMD and the recently described GSDMD inhibitor necrosulfonamide (NSA) contribute to monosodium urate (MSU) crystal-induced cell death, IL-1β release, and autoinflammation. We demonstrate that MSU crystals, the etiological agent of gout, rapidly activate GSDMD in murine macrophages. Despite this, the genetic deletion of GSD..

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Grants

Awarded by National Health and Medical Research Council of Australia


Awarded by National Institutes of Health


Awarded by National Cancer Institute Cancer Center Support Grant


Awarded by Australian Government Independent Research Institute Infrastructure Support Scheme


Funding Acknowledgements

This work was supported by National Health and Medical Research Council of Australia project grants (1145788 and 1101405), a program grant (1023407), and fellowships (1141466, 0123462, and 1105754). I.P.W. is supported by the Arthritis Foundation of Australia and the Reid Charitable Trusts; M.R. is supported by a Mathison Centenary Fellowship, The University of Melbourne; D.S.S. is supported by an inaugural Walter and Eliza Hall Institute philanthropic Ph.D. scholarship. G.S.S. and A.H. were supported by National Institutes of Health Grant GM99040 and National Cancer Institute Cancer Center Support Grant P30CA030199. This work was also supported by operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme (9000220) and the Victorian State Government Operational Infrastructure Support, Australia.