Journal Article

Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis

Van Opdenbosch, Nina, Jacques, Peggy, Fossoul, Amelie, Verheugen, Eveline, Kanneganti, Thirumala-Devi, Vande Walle, Lieselotte, Vogel, Peter, Beyaert, Rudi, Elewaut, Dirk, van Loo, Geert, Lamkanfi, Mohamed

2014

Overview

Pathogenesis of rheumatoid arthritis depends critically on the NLRP3 inflammasome/interleukin-1 signalling axis. Inflammasome-related rheumatoid arthritis model Mutations in the human NLRP3 inflammasome, a multiprotein complex involved in innate immunity through the production of certain interleukins, were previously linked to rheumatoid arthritis. Further work on the nature of this relationship has been hampered by the lack of a relevant mouse model. This study shows that the pathology in the mouse model of inflammatory arthritis induced by myeloid-specific deletion of the rheumatoid susceptibility gene A20 depends critically on the NLRP3 inflammasome and interleukin-1 signalling axis. Thus, A20 myel-KO mice provide an experimental model for the study of the role of inflammasomes in rheumatoid arthritis pathology and for testing therapies targeting inflammasomes and related cellular pathways. 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 1 , 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 2 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/21 / 13/51 / 38/39 / 631/250/262/2106/2517 / 64 / 64/60 / 82/1 / 96/95 / Animals / Apoptosis Regulatory Proteins - metabolism / Arthritis, Rheumatoid - immunology / Arthritis, Rheumatoid - metabolism / Arthritis, Rheumatoid - pathology / Arthritis, Rheumatoid - prevention & control / Autoimmune diseases / Calcium-Binding Proteins - metabolism / Carrier Proteins - metabolism / Caspase 1 - deficiency / Caspase 1 - metabolism / Cysteine Endopeptidases - deficiency / Cysteine Endopeptidases - metabolism / Dehydrogenases / Disease Models, Animal / DNA-Binding Proteins / Female / Histopathology / Humanities and Social Sciences / Inflammasomes - metabolism / Interleukin-1 - metabolism / Intracellular Signaling Peptides and Proteins - deficiency / Intracellular Signaling Peptides and Proteins - metabolism / letter / Macrophages / Macrophages - metabolism / Male / Mice / Mice, Knockout / multidisciplinary / NLR Family, Pyrin Domain-Containing 3 Protein / NLRP3 / Nuclear Proteins - metabolism / Pathogenesis / Pathology / Phenotype / Physiological aspects / Prevention / Properties / Protein expression / Proteins / Receptors, Interleukin-1 - deficiency / Receptors, Interleukin-1 - metabolism / Rheumatoid arthritis / Risk factors / Rodents / Science / Signal Transduction / Tumor Necrosis Factor alpha-Induced Protein 3