Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis
Open Access
- 23 October 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 12 (12), 1184-1193
- https://doi.org/10.1038/ni.2135
Abstract
The deubiquitinase A20 is a negative regulator of transcription factor NF-κB signaling pathways. Ma and colleagues show that mice lacking A20 expression in dendritic cells have defective lymphocyte homeostasis and develop spontaneous inflammatory disease. Dendritic cells (DCs), which are known to support immune activation during infection, may also regulate immune homeostasis in resting animals. Here we show that mice lacking the ubiquitin-editing molecule A20 specifically in DCs spontaneously showed DC activation and population expansion of activated T cells. Analysis of DC-specific epistasis in compound mice lacking both A20 and the signaling adaptor MyD88 specifically in DCs showed that A20 restricted both MyD88-independent signals, which drive activation of DCs and T cells, and MyD88-dependent signals, which drive population expansion of T cells. In addition, mice lacking A20 specifically in DCs spontaneously developed lymphocyte-dependent colitis, seronegative ankylosing arthritis and enthesitis, conditions stereotypical of human inflammatory bowel disease (IBD). Our findings indicate that DCs need A20 to preserve immune quiescence and suggest that A20-dependent DC functions may underlie IBD and IBD-associated arthritides.Keywords
This publication has 56 references indexed in Scilit:
- The Ubiquitin Modifying Enzyme A20 Restricts B Cell Survival and Prevents AutoimmunityImmunity, 2010
- Pattern Recognition Receptors and InflammationCell, 2010
- Genome-wide association scan yields new insights into the immunopathogenesis of psoriasisGenes & Immunity, 2009
- Toll-like Receptors Activate Innate and Adaptive Immunity by using Dendritic Cell-Intrinsic and -Extrinsic MechanismsImmunity, 2008
- Gene expression analysis of macrophages derived from ankylosing spondylitis patients reveals interferon‐γ dysregulationArthritis & Rheumatism, 2008
- The Ubiquitin-Editing Enzyme A20 Restricts Nucleotide-Binding Oligomerization Domain Containing 2-Triggered SignalsImmunity, 2008
- Control of Toll-like Receptor 7 Expression Is Essential to Restrict Autoimmunity and Dendritic Cell ProliferationImmunity, 2007
- Communicable Ulcerative Colitis Induced by T-bet Deficiency in the Innate Immune SystemCell, 2007
- Elimination of Antigen-Presenting Cells and Autoreactive T Cells by Fas Contributes to Prevention of AutoimmunityImmunity, 2007
- De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signallingNature, 2004