A20/Tumor Necrosis Factor α-Induced Protein 3 in Immune Cells Controls Development of Autoinflammation and Autoimmunity: Lessons from Mouse Models

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.

Modulation of allergic inflammation in the lung by a peptide derived from Mycobacteria tuberculosis chaperonin 60.1

“…It has also been shown that A20 expression is reduced in the lungs of subjects with asthma compared with healthy controls . In the present study, we have confirmed this observation demonstrating that A20 expression is significantly reduced in lung tissue biopsies, as well as in circulating leucocytes collected from patients with asthma in comparison with healthy subjects, supporting the concept that A20 is an important endogenous modulator of inflammatory responses …”

“…20 In the present study, we have confirmed this observation demonstrating that A20 expression is significantly reduced in lung tissue biopsies, as well as in circulating leucocytes collected from patients with asthma in comparison with healthy subjects, supporting the concept that A20 is an important endogenous modulator of inflammatory responses. 25,26 The role of A20 in inflammatory conditions has been well doc-…”

Astragalus polysaccharides alleviates LPS‐induced inflammation via the NF‐κB/MAPK signaling pathway

“…IL‐1α is released after tissue damage or death and participates in the inflammatory response (Afonina et al, 2011). TNFAIP3 plays important roles in innate and adaptive immune cells, including the control of necroptosis and inflammasome activity (Das, Chen, Hendriks, & Kool, 2018; Vande et al, 2014). In addition, BNIP3 is involved in various cellular processes and is considered a key regulator of apoptosis (Vasagiri & Kutala, 2014).…”

A20 is an immune tolerance factor that can determine islet transplant outcomes

“…The requirement of A20 for tissue homeostasis is highlighted by the 234 fact that the A20 locus has been associated with many autoimmune and inflammatory 235 disorders by GWAS (53). Further to this, A20 haploinsufficient human subjects present with 236 increased TH17 cells and inflammatory disease (21,22), whereas mice with A20 germline 237 deficiency succumb to uncontrolled inflammation (54). 238…”