title: The oxindole Syk inhibitor OXSI-2 blocks nigericin-induced inflammasome signaling and pyroptosis independent of potassium efflux.
abstract: The inflammasome is a caspase-1-activating complex that is implicated in a growing number of acute and chronic pathologies. Interest has increased in identifying small molecular inhibitors of inflammasome signaling because of its role in clinically relevant diseases. It was recently reported that the protein tyrosine kinase, Syk, regulates pathogen-induced inflammasome signaling by phosphorylating a molecular switch on the adapter protein ASC. However, several aspects of the role of Syk in inflammasome signaling and the effects of its inhibition remain unclear. The aim of the present study is to explore in detail the effects of the oxindole Syk inhibitor OXSI-2 on various aspects of nigericin-induced inflammasome signaling. Our results indicate that OXSI-2 inhibits inflammasome assembly, caspase-1 activation, IL-1β processing and release, mitochondrial ROS generation, and pyroptotic cell death. Using a novel live cell potassium sensor we show that Syk inhibition with OXSI-2 has no effect on potassium efflux kinetics and that blockade of potassium efflux with extracellular potassium alters Syk phosphorylation. The effects of OXSI-2 identified in this study provide context for the role of Syk in inflammasome signaling and demonstrate its importance in oxidative signaling upstream of inflammasome activation and downstream of ion flux.
authors.affiliation: Center for Biosignatures Discovery Automation, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA; Biological Design Graduate Program, School of Biological and Health Systems Engineering, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, AZ, 85287, USA.
authors.forename: Jordan R
authors.initials: JR
authors.lastname: Yaron
authors.affiliation: Center for Biosignatures Discovery Automation, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA.
authors.forename: Mounica Y
authors.initials: MY
authors.lastname: Rao
authors.affiliation: Center for Biosignatures Discovery Automation, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Gangaraju
authors.affiliation: Center for Biosignatures Discovery Automation, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Biosignatures Discovery Automation, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA.
authors.forename: Xiangxing
authors.initials: X
authors.lastname: Kong
authors.affiliation: Center for Biosignatures Discovery Automation, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA.
authors.forename: Fengyu
authors.initials: F
authors.lastname: Su
authors.affiliation: Center for Biosignatures Discovery Automation, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Center for Biosignatures Discovery Automation, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA.
authors.forename: Honor L
authors.initials: HL
authors.lastname: Glenn
authors.affiliation: Center for Biosignatures Discovery Automation, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA. Electronic address: Deirdre.Meldrum@asu.edu.
authors.forename: Deirdre R
authors.initials: DR
authors.lastname: Meldrum
mesh_terms: D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007211:Indoles / Q000008:administration & dosage*; D058847:Inflammasomes / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009550:Nigericin / Q000008:administration & dosage; D000078183:Oxindoles; D011188:Potassium / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases; D000069292:Pyroptosis / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000008:administration & dosage*; D000072377:Syk Kinase
chemical_list: C529168:3-(1-methyl-1H-indol-3-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide; D007211:Indoles; D058847:Inflammasomes; D047908:Intracellular Signaling Peptides and Proteins; D000078183:Oxindoles; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C022960:2-oxindole; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D009550:Nigericin; D011188:Potassium
keywords: Inflammasome; Inflammation; Potassium; Pyroptosis; Tyrosine kinase