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Preservation of immune quiescence in inflammatory bowel disease: the role of dendritic cell A20 expression
▶ Hammer GE, Turer EE, Taylor KE, et al. Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis. Nat Immunol 2011;12:1184–93. doi:10.1038/ni.2135
Dendritic cells (DCs) are known to play a key role in innate immune activation, but may also regulate immune homeostasis. This recent paper from Averil Ma and colleagues at the University of California, San Francisco, examined the role of the ubiquitin-editing protein A20 within DCs to identify how A20-dependent DC functions are implicated in intestinal homeostasis. A20 is a potent anti-inflammatory protein that negatively regulates the transcription factor nuclear factor kappa B by restricting signalling through several molecules including tumour necrosis factor (TNF), toll-like receptors and Nod proteins. Single nucleotide polymorphisms (SNPs) in the human A20 locus (TNFAIP3 or A20) have already been associated with several autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, psoriasis and coeliac disease, suggesting altered A20 contributes to autoimmunity. However, the current study also demonstrated that SNPs in A20 are also significantly associated with Crohn's disease. It is already known that A20-deficient mice spontaneously develop severe inflammatory disease and die perinatally. Using mice that lacked A20 expression specifically in DCs, it was demonstrated that multiple signalling pathways involved in maintaining homeostasis of myeloid and lymphoid cells are highly restricted by A20. A20-deficient DCs potently induced T cell population expansion and drove T cell-mediated colitis despite producing large amounts of the immunosuppressive cytokine, interleukin-10. Interestingly, the mice also spontaneously developed seronegative arthritis, spondyloarthritis and enthesitis, conditions that often develop in combination with human inflammatory bowel disease. The combination of disease manifestations indicated that DCs need A20 to preserve immune quiescence. In the future, the development of therapy targeting DCs, and particularly A20 functional consequences, could be considered for the management of inflammatory bowel disease.
Serotonin 5-HT2B receptor is a novel pro-regenerative and antifibrotic target in chronic liver disease
▶ Ebrahimkhani …