ArticleJournal of immunology (Baltimore, Md. : 1950)2019
The Pyroptotic Cell Death Effector Gasdermin D Is Activated by Gout-Associated Uric Acid Crystals but Is Dispensable for Cell Death and IL-1β Release.
Article in Journal of immunology (Baltimore, Md. : 1950), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 119 citations in OpenAlex.
- Cell death in ischemia-reperfusion injury: beyond a single-cell-death perspective.Biomarker research · 2026Review
- Monosodium urate crystals induce lytic macrophage death partially dependent on both pyroptosis and necroptosis.Clinical rheumatology · 2026Article
- Targeting pyroptosis to treat aortic aneurysms: From mechanism to drug discovery (Review).International journal of molecular medicine · 2026Review
- Advances in the research of gasdermin-dependent pyroptosis mechanisms and therapeutic targets in inflammatory diseases.Apoptosis : an international journal on programmed cell death · 2026Review
- Programmed cell death in gouty nephropathy: molecular mechanisms and therapeutic implications.Frontiers in immunology · 2026Review
- Delving into pyroptosis in atherosclerosis: role, mechanisms and therapeutic opportunities.Frontiers in immunology · 2026Review
- Alpha-1 Antitrypsin Mediates Spontaneous Resolution of Acute Gouty Inflammation Via Inhibiting Caspase 3/GSDME-dependent Macrophage Pyroptosis.Inflammation · 2025Article
- Porcine Epidemic Diarrhea-Virus-Induced Cell Death: Mechanistic Insights and Therapeutic Strategies.Veterinary sciences · 2025Review
- Necroptotic cell death consequences and disease relevance.Nature immunology · 2025Review
- Pyroptosis and its role in intestinal ischemia-reperfusion injury: a potential therapeutic target.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Upregulation of NLRP3 Inflammasome in Specific Hippocampal Regions: Strengthening the Link Between Neuroinflammation and Selective Vulnerability in Alzheimer's Disease.Molecular neurobiology · 2025Article
- Systemic inflammation in asymptomatic hyperuricaemia with sonographic crystal deposits, including a comparison with normouricaemia and gout.Rheumatology (Oxford, England) · 2025Article
- Divergent roles of RIPK3 and MLKL in high-fat diet-induced obesity and MAFLD in mice.Life science alliance · 2025Article
- Regulation of the NLRP3 inflammasome by autophagy and mitophagy.Immunological reviews · 2025Review
- Mechanisms of chondrocyte cell death in osteoarthritis: implications for disease progression and treatment.Journal of orthopaedic surgery and research · 2024Review
- Innate immune sensing of cell death in disease and therapeutics.Nature cell biology · 2024Review
- Gasdermin D and Gasdermin E Are Dispensable for Silica-Mediated IL-1β Secretion from Mouse Macrophages.ImmunoHorizons · 2024Article
- Cratoxylum formosum ssp. pruniflorum induces gastric cancer cell apoptosis and pyroptosis through the elevation of ROS and cell cycle arrest.Cell biochemistry and biophysics · 2024Article
- Magnesium-enriched deep-sea water inhibits NLRP3 inflammasome activation and dampens inflammation.Heliyon · 2024Article
- Characterization of Turbo, a TLR Ligand-based Adjuvant for Glycoconjugate Vaccines.ImmunoHorizons · 2024Article
17 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
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 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-1β. Consistent with in vitro findings, IL-1β 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-1β-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-1β release.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.