Publication Date:
2014-07-22
Description:
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-1beta 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-1beta. As a result, A20-deficiency in macrophages significantly enhances Nlrp3 inflammasome-mediated caspase-1 activation, pyroptosis and interleukin-1beta 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126806/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126806/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vande Walle, Lieselotte -- Van Opdenbosch, Nina -- Jacques, Peggy -- Fossoul, Amelie -- Verheugen, Eveline -- Vogel, Peter -- Beyaert, Rudi -- Elewaut, Dirk -- Kanneganti, Thirumala-Devi -- van Loo, Geert -- Lamkanfi, Mohamed -- 281600/European Research Council/International -- AI101935/AI/NIAID NIH HHS/ -- AR056296/AR/NIAMS NIH HHS/ -- CA163507/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- England -- Nature. 2014 Aug 7;512(7512):69-73. doi: 10.1038/nature13322. Epub 2014 Jun 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Medical Protein Research, VIB, Ghent B-9000, Belgium [2] Department of Biochemistry, Ghent University, Ghent B-9000, Belgium. ; Department of Rheumatology, Ghent University, Ghent B-9000, Belgium. ; Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] Inflammation Research Center, VIB, Ghent B-9052, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium. ; 1] Inflammation Research Center, VIB, Ghent B-9052, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium [3]. ; 1] Department of Medical Protein Research, VIB, Ghent B-9000, Belgium [2] Department of Biochemistry, Ghent University, Ghent B-9000, Belgium [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043000" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Apoptosis Regulatory Proteins/metabolism
;
Arthritis, Rheumatoid/immunology/*metabolism/pathology/prevention & control
;
Calcium-Binding Proteins/metabolism
;
Carrier Proteins/*metabolism
;
Caspase 1/deficiency/metabolism
;
Cysteine Endopeptidases/deficiency/*metabolism
;
DNA-Binding Proteins
;
Disease Models, Animal
;
Female
;
Inflammasomes/*metabolism
;
Interleukin-1/metabolism
;
Intracellular Signaling Peptides and Proteins/deficiency/*metabolism
;
Macrophages/metabolism
;
Male
;
Mice
;
Mice, Knockout
;
Nuclear Proteins/metabolism
;
Phenotype
;
Receptors, Interleukin-1/deficiency/metabolism
;
Signal Transduction
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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