Abstract
Immune cell activation is a stringently regulated process, as exaggerated innate and adaptive immune responses can lead to autoinflammatory and autoimmune diseases. Perhaps the best-characterized molecular pathway promoting cell activation is the nuclear factor-κB (NF-κB) signaling pathway. Stimulation of this pathway leads to transcription of numerous pro-inflammatory and cell-survival genes. Several mechanisms tightly control NF-κB activity, including the key regulatory zinc finger (de)ubiquitinating enzyme A20/tumor necrosis factor α-induced protein 3 (TNFAIP3). Single nucleotide polymorphisms (SNPs) in the vicinity of the TNFAIP3 gene are associated with a spectrum of chronic systemic inflammatory diseases, indicative of its clinical relevance. Mice harboring targeted cell-specific deletions of the Tnfaip3 gene in innate immune cells such as macrophages spontaneously develop autoinflammatory disease. When immune cells involved in the adaptive immune response, such as dendritic cells or B-cells, are targeted for A20/TNFAIP3 deletion, mice develop spontaneous inflammation that resembles human autoimmune disease. Therefore, more knowledge on A20/TNFAIP3 function in cells of the immune system is beneficial in our understanding of autoinflammation and autoimmunity. Using the aforementioned mouse models, novel A20/TNFAIP3 functions have recently been described including control of necroptosis and inflammasome activity. In this review, we discuss the function of the A20/TNFAIP3 enzyme and its critical role in various innate and adaptive immune cells. Finally, we discuss the latest findings on TNFAIP3 SNPs in human autoinflammatory and autoimmune diseases and address that genotyping of TNFAIP3 SNPs may guide treatment decisions.
Highlights
Autoinflammatory and autoimmune diseases share a spectrum of chronic immune system disorders [1]
Genetic studies have demonstrated the association of tumor necrosis factor α-induced protein 3 (TNFAIP3) single nucleotide polymorphisms (SNPs) with multiple human diseases [7], such as systemic lupus erythematosus (SLE) [8,9,10], rheumatoid arthritis (RA) [9], and Crohn’s disease (CD) [11, 12]
Since a comprehensive overview of SNPs within and around the TNFAIP3 gene has been provided elsewhere [7], we focus on a selection of SNPs with known different functional, clinical, and therapeutical consequences (Figure 2)
Summary
Autoinflammatory and autoimmune diseases share a spectrum of chronic immune system disorders [1]. Cell-extrinsic factors control A20/ TNFAIP3 protein stability, e.g., high glucose levels target A20/ TNFAIP3 for proteasomal degradation and/or reactive oxygen species (ROS) inactivate its deubiquitinating activity [52,53,54]. The latter is important in RA, in which elevated ROS plays a pathogenic role [55, 56], possibly by inhibiting A20/ TNFAIP3 function. Summarizing, A20/TNFAIP3 in B-cells controls co-stimulatory molecule expression, IL-6 production, and Bcl-x survival protein expression, thereby preventing autoreactive B-cells formation resulting in an autoimmune SLE phenotype. Specific SNPs functionally alter A20/TNFAIP3 expression or function, and HA20 is a disease with generalized inflammation due to severely reduced functional A20/TNFAIP3 protein expression
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