title: TLR activation regulates damage-associated molecular pattern isoforms released during pyroptosis.
abstract: Infection of macrophages by bacterial pathogens can trigger Toll-like receptor (TLR) activation as well as Nod-like receptors (NLRs) leading to inflammasome formation and cell death dependent on caspase-1 (pyroptosis). Complicating the study of inflammasome activation is priming. Here, we develop a priming-free NLRC4 inflammasome activation system to address the necessity and role of priming in pyroptotic cell death and damage-associated molecular pattern (DAMP) release. We find pyroptosis is not dependent on priming and when priming is re-introduced pyroptosis is unaffected. Cells undergoing unprimed pyroptosis appear to be independent of mitochondrial involvement and do not produce inflammatory cytokines, nitrous oxide (NO), or reactive oxygen species (ROS). Nevertheless, they undergo an explosive cell death releasing a chemotactic isoform of the DAMP high mobility group protein box 1 (HMGB1). Importantly, priming through surface TLRs but not endosomal TLRs during pyroptosis leads to the release of a new TLR4-agonist cysteine redox isoform of HMGB1. These results show that pyroptosis is dominant to priming signals and indicates that metabolic changes triggered by priming can affect how cell death is perceived by the immune system.
authors.affiliation: Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Sanna
authors.initials: S
authors.lastname: Nyström
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Antoine
authors.forename: Peter
authors.initials: P
authors.lastname: Lundbäck
authors.forename: John G
authors.initials: JG
authors.lastname: Lock
authors.forename: Andreia F
authors.initials: AF
authors.lastname: Nita
authors.forename: Kari
authors.initials: K
authors.lastname: Högstrand
authors.forename: Alf
authors.initials: A
authors.lastname: Grandien
authors.forename: Helena
authors.initials: H
authors.lastname: Erlandsson-Harris
authors.forename: Ulf
authors.initials: U
authors.lastname: Andersson
authors.forename: Steven E
authors.initials: SE
authors.lastname: Applequist
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D015870:Gene Expression; D024243:HMGB1 Protein / Q000032:analysis / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; D002135:Calcium-Binding Proteins; D024243:HMGB1 Protein; D058847:Inflammasomes; C512299:Ipaf protein, mouse; C496806:Naip5 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein; D020033:Protein Isoforms; D051193:Toll-Like Receptors; D020170:Caspase 1