Mini Review ARTICLE
A20/TNFAIP3 in immune cells controls development of autoinflammation and autoimmunity: Lessons from mouse models
- 1Pulmonary Medicine, Erasmus Medical Center, Erasmus University Rotterdam, Netherlands
Immune cell activation is a stringently regulated process, as exaggerated innate and adaptive immune responses can lead to autoinflammatory and autoimmune diseases. Autoinflammation and autoimmunity are mediated by aberrantly activated immune cells, either innate or adaptive immune cells.
Perhaps the best-characterized molecular pathway in immune cell activation is the nuclear factor-κB (NF-κB) signalling pathway leading to transcription of numerous pro-inflammatory and cell-survival genes. NF-κB activation is tightly controlled by several mechanisms, including the key regulatory zinc-finger (de)ubiquitinating enzyme A20/TNFAIP3. Single nucleotide polymorphisms (SNPs) in the vicinity of the TNFAIP3 gene are associated with a spectrum of chronic systemic inflammatory diseases, indicating its clinical relevance. Mice harboring targeted cell-specific deletions of the Tnfaip3 gene in innate immune cells like macrophages spontaneously develop autoinflammatory disease. In contrast, when immune cells involved in the adaptive immune response, like dendritic cells or B-cells are targeted for A20/TNFAIP3 deletion, mice develop spontaneous inflammation that resemble human autoimmune disease. Therefore, more knowledge on A20/TNFAIP3 function in innate and adaptive immune cells is beneficial in our understanding of autoinflammation and autoimmunity. Using the above mentioned mouse models, novel A20/TNFAIP3 functions have recently been described such as 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. Lastly, we discuss the latest findings on A20/TNFAIP3 SNPs in human autoinflammatory and autoimmune diseases and address that genotyping of TNFAIP3 SNPs may guide treatment decisions.
Keywords: A20, TNFAIP3, NF-κB, Ubiquitination, autoimmune disease, mouse models, SNP, Autoinflammation
Received: 03 Nov 2017;
Accepted: 12 Jan 2018.
Edited by:Massimo Gadina, National Institute of Arthritis and Musculoskeletal and Skin Diseases, United States
Reviewed by:Ivona Aksentijevich, National Human Genome Research Institute (NIH), United States
Michael F. McDermott, University of Leeds, United Kingdom
Copyright: © 2018 Das, Chen, Hendriks and Kool. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Mirjam Kool, Erasmus Medical Center, Erasmus University Rotterdam, Pulmonary Medicine, Wytemaweg 80, Rotterdam, 3015 CN, Netherlands, firstname.lastname@example.org