Advanced search
1 file | 2.17 MB

Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis

(2014) NATURE. 512(7512). p.69-73
Author
Organization
Project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
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(1), but our understanding of the upstream mechanisms leading to production of interleukin-1 beta 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 A 20 have increased basal and lipopolysaccharide-induced expression levels of the inflammasome adaptor Nlrp3 and proIL-beta b. As a result, A 20-deficiency in macrophages significantly enhances Nlrp3 inflammasome- mediated caspase-1 activation, pyroptosis and interleukin-1 beta 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 A(20myel-KO) mice as the first experimental model to study the role of inflammasomes in the pathology of rheumatoid arthritis.
Keywords
RHEUMATOID-ARTHRITIS, SUSCEPTIBILITY, MICE, ASSOCIATION, 6Q23, INHIBITOR, ACTIVATION, NF-KAPPA-B, COLLAGEN-INDUCED ARTHRITIS, CASPASE-1

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 2.17 MB

Citation

Please use this url to cite or link to this publication:

Chicago
Vande Walle, Lieselotte, Nina Van Opdenbosch, Peggy Jacques, Amelie Fossoul, Eveline Verheugen, Peter Vogel, Rudi Beyaert, et al. 2014. “Negative Regulation of the NLRP3 Inflammasome by A20 Protects Against Arthritis.” Nature 512 (7512): 69–73.
APA
Vande Walle, L., Van Opdenbosch, N., Jacques, P., Fossoul, A., Verheugen, E., Vogel, P., Beyaert, R., et al. (2014). Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. NATURE, 512(7512), 69–73.
Vancouver
1.
Vande Walle L, Van Opdenbosch N, Jacques P, Fossoul A, Verheugen E, Vogel P, et al. Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. NATURE. 2014;512(7512):69–73.
MLA
Vande Walle, Lieselotte, Nina Van Opdenbosch, Peggy Jacques, et al. “Negative Regulation of the NLRP3 Inflammasome by A20 Protects Against Arthritis.” NATURE 512.7512 (2014): 69–73. Print.
@article{5720510,
  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(1), but our understanding of the upstream mechanisms leading to production of interleukin-1 beta 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 A 20 have increased basal and lipopolysaccharide-induced expression levels of the inflammasome adaptor Nlrp3 and proIL-beta b. As a result, A 20-deficiency in macrophages significantly enhances Nlrp3 inflammasome- mediated caspase-1 activation, pyroptosis and interleukin-1 beta 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 A(20myel-KO) mice as the first experimental model to study the role of inflammasomes in the pathology of rheumatoid arthritis.},
  author       = {Vande Walle, Lieselotte and Van Opdenbosch, Nina and Jacques, Peggy and Fossoul, Amelie and Verheugen, Eveline and Vogel, Peter and Beyaert, Rudi and Elewaut, Dirk and Kanneganti, Thirumala-Devi and van Loo, Geert and Lamkanfi, Mohamed},
  issn         = {0028-0836},
  journal      = {NATURE},
  keywords     = {RHEUMATOID-ARTHRITIS,SUSCEPTIBILITY,MICE,ASSOCIATION,6Q23,INHIBITOR,ACTIVATION,NF-KAPPA-B,COLLAGEN-INDUCED ARTHRITIS,CASPASE-1},
  language     = {eng},
  number       = {7512},
  pages        = {69--73},
  title        = {Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis},
  url          = {http://dx.doi.org/10.1038/nature13322},
  volume       = {512},
  year         = {2014},
}

Altmetric
View in Altmetric
Web of Science
Times cited: