title: Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice.
abstract: Inflammasomes are protein complexes that promote caspase activation, resulting in processing of IL-1β and cell death, in response to infection and cellular stresses. Inflammasomes have been anticipated to contribute to autoimmunity. The New Zealand Black (NZB) mouse develops anti-erythrocyte Abs and is a model of autoimmune hemolytic anemia. These mice also develop anti-nuclear Abs typical of lupus. In this article, we show that NZB macrophages have deficient inflammasome responses to a DNA virus and fungal infection. Absent in melanoma 2 (AIM2) inflammasome responses are compromised in NZB by high expression of the AIM 2 antagonist protein p202, and consequently NZB cells had low IL-1β output in response to both transfected DNA and mouse CMV infection. Surprisingly, we also found that a second inflammasome system, mediated by the NLR family, pyrin domain containing 3 (NLRP3) initiating protein, was completely lacking in NZB cells. This was due to a point mutation in an intron of the Nlrp3 gene in NZB mice, which generates a novel splice acceptor site. This leads to incorporation of a pseudoexon with a premature stop codon. The lack of full-length NLRP3 protein results in NZB being effectively null for Nlrp3, with no production of bioactive IL-1β in response to NLRP3 stimuli, including infection with Candida albicans. Thus, this autoimmune strain harbors two inflammasome deficiencies, mediated through quite distinct mechanisms. We hypothesize that the inflammasome deficiencies in NZB alter the interaction of the host with both microflora and pathogens, promoting prolonged production of cytokines that contribute to development of autoantibodies.
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia; katryn.stacey@uq.edu.au d.sester@uq.edu.au.
authors.forename: David P
authors.initials: DP
authors.lastname: Sester
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia;
authors.forename: Vitaliya
authors.initials: V
authors.lastname: Sagulenko
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia;
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Thygesen
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia;
authors.forename: Jasmyn A
authors.initials: JA
authors.lastname: Cridland
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia;
authors.forename: Yen Siew
authors.initials: YS
authors.lastname: Loi
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia;
authors.forename: Simon O
authors.initials: SO
authors.lastname: Cridland
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia;
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia;
authors.forename: Ulrich
authors.initials: U
authors.lastname: Genske
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53127, Bonn, Germany;
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley 6009, Western Australia, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands 6009, Western Australia, Australia; and.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Andoniou
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Queensland, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley 6009, Western Australia, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands 6009, Western Australia, Australia; and.
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Queensland, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Schroder
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Queensland, Australia katryn.stacey@uq.edu.au d.sester@uq.edu.au.
authors.forename: Katryn J
authors.identifier: http://orcid.org/0000-0002-3992-7802
authors.initials: KJ
authors.lastname: Stacey
mesh_terms: D000744:Anemia, Hemolytic, Autoimmune / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D002176:Candida albicans / Q000276:immunology; D002177:Candidiasis / Q000276:immunology / Q000382:microbiology; D002352:Carrier Proteins / Q000235:genetics* / Q000276:immunology; D020170:Caspase 1 / Q000235:genetics; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000821:virology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D058847:Inflammasomes / Q000235:genetics* / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008814:Mice, Inbred NZB; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: C540422:Aim2 protein, mouse; D000974:Antibodies, Antinuclear; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C587672:IL1B protein, mouse; C092537:Ifi202b protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020170:Caspase 1