title: Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.
abstract: Rheumatoid arthritis is a chronic autoinflammatory disease that affects 1-2% of the world's population and is characterized by widespread joint inflammation. Interleukin-1 is an important mediator of cartilage destruction in rheumatic diseases, but our understanding of the upstream mechanisms leading to production of interleukin-1β in rheumatoid arthritis is limited by the absence of suitable mouse models of the disease in which inflammasomes contribute to pathology. Myeloid-cell-specific deletion of the rheumatoid arthritis susceptibility gene A20/Tnfaip3 in mice (A20(myel-KO) mice) triggers a spontaneous erosive polyarthritis that resembles rheumatoid arthritis in patients. Rheumatoid arthritis in A20(myel-KO) mice is not rescued by deletion of tumour necrosis factor receptor 1 (ref. 2). Here we show, however, that it crucially relies on the Nlrp3 inflammasome and interleukin-1 receptor signalling. Macrophages lacking A20 have increased basal and lipopolysaccharide-induced expression levels of the inflammasome adaptor Nlrp3 and proIL-1β. As a result, A20-deficiency in macrophages significantly enhances Nlrp3 inflammasome-mediated caspase-1 activation, pyroptosis and interleukin-1β secretion by soluble and crystalline Nlrp3 stimuli. In contrast, activation of the Nlrc4 and AIM2 inflammasomes is not altered. Importantly, increased Nlrp3 inflammasome activation contributes to the pathology of rheumatoid arthritis in vivo, because deletion of Nlrp3, caspase-1 and the interleukin-1 receptor markedly protects against rheumatoid-arthritis-associated inflammation and cartilage destruction in A20(myel-KO) mice. These results reveal A20 as a novel negative regulator of Nlrp3 inflammasome activation, and describe A20(myel-KO) mice as the first experimental model to study the role of inflammasomes in the pathology of rheumatoid arthritis.
authors.affiliation: Department of Medical Protein Research, VIB, Ghent, B-9000, Belgium.|Department of Biochemistry, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Lieselotte
authors.initials: L
authors.lastname: Vande Walle
authors.affiliation: Department of Medical Protein Research, VIB, Ghent, B-9000, Belgium.|Department of Biochemistry, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Nina
authors.initials: N
authors.lastname: Van Opdenbosch
authors.affiliation: Department of Rheumatology, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Peggy
authors.initials: P
authors.lastname: Jacques
authors.affiliation: Department of Medical Protein Research, VIB, Ghent, B-9000, Belgium.|Department of Biochemistry, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Amelie
authors.initials: A
authors.lastname: Fossoul
authors.affiliation: Department of Rheumatology, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Eveline
authors.initials: E
authors.lastname: Verheugen
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Inflammation Research Center, VIB, Ghent, B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: Department of Rheumatology, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.affiliation: Inflammation Research Center, VIB, Ghent, B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.affiliation: Department of Medical Protein Research, VIB, Ghent, B-9000, Belgium.|Department of Biochemistry, Ghent University, Ghent, B-9000, Belgium.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000172:deficiency / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D058847:Inflammasomes / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; D017472:Receptors, Interleukin-1; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse; D020170:Caspase 1