title: A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis.
abstract: A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-κB signaling in response to specific proinflammatory stimuli in different cell types and has been suggested as a susceptibility gene for rheumatoid arthritis. To define the contribution of A20 to rheumatoid arthritis pathology, we generated myeloid-specific A20-deficient mice and show that specific ablation of Tnfaip3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis. Myeloid-A20-deficient mice have high levels of inflammatory cytokines in their serum, consistent with a sustained NF-κB activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 and IL-6 dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Together, these observations indicate a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis, supporting the idea of developing A20 modulatory drugs as cell-targeted therapies.
authors.affiliation: Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, Vlaams Instituut voor Biotechnologie, Ghent, Belgium.
authors.forename: Mourad
authors.initials: M
authors.lastname: Matmati
authors.forename: Peggy
authors.initials: P
authors.lastname: Jacques
authors.forename: Jonathan
authors.initials: J
authors.lastname: Maelfait
authors.forename: Eveline
authors.initials: E
authors.lastname: Verheugen
authors.forename: Mirjam
authors.initials: M
authors.lastname: Kool
authors.forename: Mozes
authors.initials: M
authors.lastname: Sze
authors.forename: Lies
authors.initials: L
authors.lastname: Geboes
authors.forename: Els
authors.initials: E
authors.lastname: Louagie
authors.forename: Conor
authors.initials: C
authors.lastname: Mc Guire
authors.forename: Lars
authors.initials: L
authors.lastname: Vereecke
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chu
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Steven
authors.initials: S
authors.lastname: Staelens
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthys
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D003546:Cysteine Endopeptidases / Q000235:genetics*; D016207:Cytokines / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse