Inflammasome inhibition blocks cardiac glycoside cell toxicity

• Type of Material: Article
• Authors: Doris L. LaRock, University of California San Diego; Jenna S. Sands, Emory University; Ethan Ettouati, University of California San Diego; Marine Richard, University of California San Diego; Paul J. Bushway, University of California San Diego; Eric D. Adler, University of California San Diego; Victor Nizet, University of California San Diego; Christopher LaRock, Emory University
• Language: English
• Date: 2019-08-23
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2019 LaRock et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.RA119.008330
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 294
• Issue: 34
• Start Page: 12846
• End Page: 12854
• Grant/Funding Information: This work was supported, in whole or in part, by NICHD, National Institutes of Health Grant HD090259 (to V.N.) and NIAID, National Institutes of Health Grant AI130223 (to C. N. L.).
• Keywords: caspase 1 (CASP1); Biochemistry & Molecular Biology; PYROPTOSIS; ACTIVATION; DIGOXIN; HEART-FAILURE; inflammasome; macrophage; IL-1; MORTALITY; NERIUM-OLEANDER; NLRP3 INFLAMMASOME; ASSOCIATION; RECRUITMENT; cardiomyocyte; cell death; cardiac glycoside; Life Sciences & Biomedicine; IL-1-BETA; Science & Technology
• Research Categories: Health Sciences, Toxicology; Biology, Cell

Abstract

Chronic heart failure and cardiac arrhythmias have high morbidity and mortality, and drugs for the prevention and management of these diseases are a large part of the pharmaceutical market. Among these drugs are plant-derived cardiac glycosides, which have been used by various cultures over millennia as both medicines and poisons.Wereport that digoxin and related compounds activate the NLRP3 inflammasome in macrophages and cardiomyocytes at concentrations achievable during clinical use. Inflammasome activation initiates the maturation and release of the inflammatory cytokine IL-1β and the programmed cell death pathway pyroptosis in a caspase-1-dependent manner. Notably, the same fluxes of potassium and calcium cations that affect heart contraction also induce inflammasome activation in human but not murine cells. Pharmaceuticals that antagonize these fluxes, including glyburide and verapamil, also inhibit inflammasome activation by cardiac glycosides. Cardiac glycoside-induced cellular cytotoxicity and IL-1β signaling are likewise antagonized by inhibitors of the NLRP3 inflammasome or the IL-1 receptor-targeting biological agent anakinra. Our results inform on the molecular mechanism by which the inflammasome integrates the diverse signals that activate it through secondary signals like cation flux. Furthermore, this mechanism suggests a contribution of the inflammasome to the toxicity and adverse events associated with cardiac glycosides use in humans and that targeted anti-inflammatories could provide an additional adjunct therapeutic countermeasure.