title: Caspase-4 mediates non-canonical activation of the NLRP3 inflammasome in human myeloid cells.
abstract: Inflammasome activation culminates in activation of caspase-1, which leads to the maturation and subsequent release of cytokines of the interleukin 1 (IL-1) family and results in a particular form of cell death known as pyroptosis. In addition, in the murine system, a so-called non-canonical inflammasome involving caspase-11 has been described that directly responds to cytosolic LPS. Here, we show that the human monocytic cell line THP1 activates the inflammasome in response to cytosolic LPS in a TLR4-independent fashion. This response is mediated by caspase-4 and accompanied by caspase-1 activation, pyroptosis, and IL-1β maturation. In addition to caspase-4, efficient IL-1β conversion upon intracellular LPS delivery relies on potassium efflux, NLRP3, ASC, and caspase-1, indicating that although caspase-4 activation alone is sufficient to induce pyroptosis, this process depends on the NLRP3 inflammasome activation to drive IL-1β maturation. Altogether, this study provides evidence for the presence of a non-canonical inflammasome in humans and its dependence on caspase-4.
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Schmid-Burgk
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Moritz M
authors.initials: MM
authors.lastname: Gaidt
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Ebert
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany.|Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Bartok
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D053471:Caspases, Initiator / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D002352:Carrier Proteins; C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C093516:CASP4 protein, human; D053471:Caspases, Initiator; D020170:Caspase 1
keywords: Caspase-4; Myeloid cells; NLRP3; Non-canonical inflammasome