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Nature. 2014 Aug 7;512(7512):69-73. doi: 10.1038/nature13322. Epub 2014 Jun 29.

Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.

Author information

1
Department of Medical Protein Research, VIB, Ghent, B-9000, Belgium.
2
Department of Biochemistry, Ghent University, Ghent, B-9000, Belgium.
3
Department of Rheumatology, Ghent University, B-9000 Ghent, Belgium.
4
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
5
Inflammation Research Center, VIB, Ghent, B-9052, Belgium.
6
Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
#
Contributed equally

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.

PMID:
25043000
PMCID:
PMC4126806
DOI:
10.1038/nature13322
[Indexed for MEDLINE]
Free PMC Article

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