title: The murine neutrophil NLRP3 inflammasome is activated by soluble but not particulate or crystalline agonists.
abstract: Neutrophils express pattern recognition receptors (PRRs) and regulate immune responses via PRR-dependent cytokine production. An emerging theme is that neutrophil PRRs often exhibit cell type-specific adaptations in their signalling pathways. This prompted us to examine inflammasome signalling by the PRR NLRP3 in murine neutrophils, in comparison to well-established NLRP3 signalling pathways in macrophages. Here, we demonstrate that while murine neutrophils can indeed signal via the NLRP3 inflammasome, neutrophil NLRP3 selectively responds to soluble agonists but not to the particulate/crystalline agonists that trigger NLRP3 activation in macrophages via phagolysosomal rupture. In keeping with this, alum did not trigger IL-1β production from human PMN, and the lysosomotropic peptide Leu-Leu-OMe stimulated only weak NLRP3-dependent IL-1β production from murine neutrophils, suggesting that lysosomal rupture is not a strong stimulus for NLRP3 activation in neutrophils. We validated our in vitro findings for poor neutrophil NLRP3 responses to particles in vivo, where we demonstrated that neutrophils do not significantly contribute to alum-induced IL-1β production in mice. In all, our studies highlight that myeloid cell identity and the nature of the danger signal can strongly influence signalling by a single PRR, thus shaping the nature of the resultant immune response.
authors.affiliation: Institute for Molecular Bioscience and Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, Australia.
authors.forename: Kaiwen W
authors.initials: KW
authors.lastname: Chen
authors.affiliation: Institute for Molecular Bioscience and Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, Australia.
authors.forename: Jelena S
authors.initials: JS
authors.lastname: Bezbradica
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Groß
authors.affiliation: Institute for Molecular Bioscience and Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, Australia.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Wall
authors.affiliation: Institute for Molecular Bioscience and Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
authors.affiliation: Institute for Molecular Bioscience and Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stow
authors.affiliation: Institute for Molecular Bioscience and Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Schroder
mesh_terms: D000534:Alum Compounds / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology; D051192:Receptors, Pattern Recognition / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000534:Alum Compounds; D002352:Carrier Proteins; D004151:Dipeptides; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D051192:Receptors, Pattern Recognition; C045139:leucyl-leucine-methyl ester; C041524:aluminum sulfate
keywords: IL-1β · Inflammasomes · Lysosomal rupture · Neutrophils · NLRP3