Inflammatory autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, psoriasis, and multiple sclerosis are amongst the most common diseases. Their prevalence has been rapidly expanding over the last few decades, which means that currently millions of patients are under constant treatment with anti-inflammatory drugs to keep their condition under control. As an example, about 1% of the western population is affected by rheumatoid arthritis (RA), a chronic and progressive inflammatory disease of the joints that severely affects the patients’ quality of life. The molecular mechanisms that cause diseases such as RA need to be better understood in order to be able to develop new therapies to treat patients suffering from inflammatory pathologies. Now a study by the research team of Prof. Geert van Loo (VIB-UGent Center for Inflammation Research) has unraveled a critical molecular mechanism behind autoimmune and inflammatory diseases such as rheumatoid arthritis, Crohn’s disease, and psoriasis. They discovered how the protein A20 prevents inflammation and autoimmunity, not through its enzymatic activities as has been proposed, but through a non-enzymatic mechanism. These findings open up new possibilities for the treatment of inflammatory diseases. The results of the study are published in the prestigious journal Nature Immunology.
Many autoimmunity conditions see the participation of cytokines like several interleukins and the tumor necrosis factor alpha (TNF-alpha). TNF is a well-established inducer of inflammation, and a pharmacological target in several inflammatory disorders. Binding of TNF to TNFR1 induces the rapid assembly of a membrane-bound signaling complex. The initial binding of TRADD and RIPK1 to the receptor allows the subsequent recruitment of TRAF2 and other proteins. Together, these generate a dense network of protein “tagging” resulting in the stabilization of the receptor complex itself and in the activation of the MAPKs and NF-κB signaling pathways. The pathologic role of TNF in inflammatory disorders has long been attributed to the MAPK/NF-κB-dependent induction of inflammatory mediators, but recent studies in mice have demonstrated that TNF also indirectly causes inflammation by inducing cell death. One molecular brake to cell death is the A20 protein. Mutations in the gene encoding A20 are associated with a wide panel of inflammatory pathologies, both in in the mouse and man. Apart from functioning as an inhibitor of the NF-κB pathway, A20 is also known to potently inhibit TNF toxicity. This suggests that the inflammatory disorders associated with mutations in A20 may be caused, at least in part, by excessive cell death induction.
Arne Martens in the research group of Prof. Geert van Loo investigated the molecular signaling mechanism by which the protein A20 controls inflammatory reactions. The current study builds further upon earlier work at the VIB-UGent Center for Inflammation Research which demonstrated that A20 acts as a strong anti-inflammatory mediator in many models of inflammatory disease. In this study, the researchers show that the anti-inflammatory activity of A20 depends on the presence of a specific domain within the protein that is able to bind to ubiquitin, the miniprotein that “tags” proteins. This allows A20 to interfere with signaling pathways within the cell and as such prevent the activation of a cellular response that would normally result in inflammation and disease development. Prof. van Loo explains the importance of their findings: “Our results are important from a scientific point of view since they help us understand how A20 prevents inflammatory reactions in the body’s cells. However, this knowledge also has therapeutic implications, and suggests that drugs based on that specific A20 domain could have strong anti-inflammatory activities. Therefore, such drugs could be effective in the treatment of RA and various other inflammatory and autoimmune diseases”.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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