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The pyroptotic cell death effector gasdermin D Is activated by gout-associated uric acid crystals but is dispensable for cell death and IL-1beta release


Rashidi, M; Simpson, DS; Hempel, A; Frank, D; Petrie, E; Vince, A; Feltham, R; Murphy, J; Chatfield, SM; Salvesen, GS; Murphy, JM; Wicks, IP; Vince, JE
2019-08
2019-06-17
Journal of Immunology
Journal Article
203
3
736-748
The pyroptotic cell death effector gasdermin D (GSDMD) is required for murine models of hereditary inflammasome-driven, IL-1beta-dependent, autoinflammatory disease, making it an attractive therapeutic target. However, the importance of GSDMD for more common conditions mediated by pathological IL-1beta 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-1beta 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 GSDMD or the other lytic effector implicated in MSU crystal killing, mixed lineage kinase domain-like (MLKL), did not prevent MSU crystal-induced cell death. Consequently, GSDMD or MLKL loss did not hinder MSU crystal-mediated release of bioactive IL-1beta. Consistent with in vitro findings, IL-1beta induction and autoinflammation in MSU crystal-induced peritonitis was not reduced in GSDMD-deficient mice. Moreover, we show that the reported GSDMD inhibitor, NSA, blocks inflammasome priming and caspase-1 activation, thereby preventing pyroptosis independent of GSDMD targeting. The inhibition of cathepsins, widely implicated in particle-induced macrophage killing, also failed to prevent MSU crystal-mediated cell death. These findings 1) demonstrate that not all IL-1beta-driven autoinflammatory conditions will benefit from the therapeutic targeting of GSDMD, 2) document a unique mechanism of MSU crystal-induced macrophage cell death not rescued by pan-cathepsin inhibition, and 3) show that NSA inhibits inflammasomes upstream of GSDMD to prevent pyroptotic cell death and IL-1beta release.
ASI
Inflammation
10.4049/jimmunol.1900228
31209100
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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Creation Date 2019-06-20 10:18:10 Last Modified 2019-07-25 11:44:43