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.

A20 controls intestinal homeostasis through cell-specific activities

“…The functions of A20 are diverse and cell type-dependent: myeloid cells require A20 to prevent their spontaneous hyperactivation and expansion 9 , while IECs need A20 as a protective factor maintaining barrier stability in inflammatory conditions 8 . Although single IEC or myeloid deletion does not cause spontaneous intestinal defects, double IEC and myeloid A20 deficiency induces spontaneous intestinal pathology due to hyperinflammatory A20-deficient myeloid cells causing epithelial apoptosis and progressive loss of Paneth and goblet cells.…”

“…In contrast, A20 myel-KO mice develop rheumatoid arthritis-like symptoms, but not colitis, due to hyperactivated myeloid cells producing elevated levels of inflammatory cytokines, including TNF and interleukin-6 (IL-6) (ref. 9). Combined IEC and myeloid A20 deficiency (A20 IEC/myel-KO ) fully recapitulates the inflammatory phenotype of A20 myel-KO mice, showing myeloid cell expansion with lymphadenopathy and splenomegaly, and increased levels of TNF and IL-6 in their serum ( Supplementary Fig.…”

“…7a, Supplementary Table 1). Although A20 myel-KO mice have no spontaneous intestinal phenotype, the observed dysbiosis may be linked to the rheumatoid arthritis-like phenotype of these mice 9 . Indeed, studies have shown that the inflammatory status of the host is inversely correlated to the richness of its microbial communities 21,22 .…”

“…Although A20 is indispensable to maintain barrier integrity in conditions of inflammation, A20 IEC-KO mice do not spontaneously develop intestinal inflammation 8 . Similarly, although mice with myeloid cell-specific deletion of A20 (A20 myel-KO ) develop rheumatoid arthritis-like symptoms due to excessive NF-kB activation and inflammatory responses, they do not develop spontaneous intestinal pathology 9 . The absence of any spontaneously developing intestinal phenotype in A20 IEC-KO or A20 myel-KO may therefore question the role of A20 in human IBD as originally suggested by human genetic studies [4][5][6] .…”

Deubiquitylases From Genes to Organism

“…This provides a framework for understanding the role of A20 in suppressing B-cell lymphomas, which is suggested by human genetic studies (36,96,161). Other studies have found critical functions for A20 in dendritic cells (83,126), macrophages (167), and intestinal epithelial cells (265).…”