Inflammasome research provides insight into rheumatoid arthritis

22 September 2014
​Lieselotte Vande Walle and Mo Lamkanfi (VIB Department of Medical Protein Research, UGent) demonstrated with their inflammasome research that rheumatoid arthritis should be considered a syndrome rather than a disease. In the process, they proved that the A20 KO mouse is a perfect model for research on inflammasomes and RA.

How important are your findings?
Mo: They are important because for the first time a mouse model for RA has been described in which the illness is mainly driven by inflammasome signaling. Earlier studies, including a number of them in which we participated, have shown that all the RA mouse models that are commonly used in research around the world, such as the collagen-induced CIA model, the antigen-induced RA model and the passive serum transfer model, develop the disease via mechanisms unrelated to inflammasome signaling. So the A20LysM-Cre model is perfectly suited for validating new therapies based on inflammasome signal interference in RA before starting clinical trials with them.

Why are you so intrigued with inflammasomes?
Inflammasome research is one of the spearheads of international immunological research. Research in this field dates back only 10 years or so. Nevertheless, it has already produced major breakthroughs that have significantly changed our understanding of the immune system and led to new therapeutic options for patients. The interest in these signaling pathways has grown enormously with the realization that mutations in components of these mechanisms lead to all kinds of autoimmune and auto-inflammatory conditions in patients. There are also strong links to Type 2 diabetes, atherosclerosis and neurodegenerative diseases such as Alzheimer’s. In spite of these breakthroughs, however, major questions remain.

Already as a PhD student in the lab of Peter Vandenabeele (IRC, VIB/UGent) I was studying caspase 1, one of the main inflammatory proteases controlled by these inflammasomes. I made a conscious decision to pursue postdoc studies in the emerging field of NOD-like receptors and inflammasomes—research that, at the time, was mainly advanced in the US. To develop my own expertise in this field, I worked with Gabriel Nuñez (University of Michigan) and Vishva Dixit (Genentech). Then, with these new skills under my belt and the much appreciated support of Joël Vandekerckhove and Walter Fiers, I was able to set up my own research group for it within VIB.

How did you end up working with the A20KO mouse of Geert van Loo and Rudi Beyaert (IRC)?
At the start we often worked with the traditional RA mouse models for our research on the role of inflammasomes. That's how we learned that in the CIA model inflammasomes are of no consequence to the development of the disease. During that same period, colleagues in Switzerland and the Netherlands discovered that inflammasomes were not critical in other RA mouse models, either.

Shortly after my return to Europe, Geert van Loo and Rudi Beyaert published their A20-RA model. They demonstrated at the same time that TNF, an important molecule in other RA models, did not control the disease in this model. This suggested that other mechanisms controlled the disease in the A20 RA model. This led us to study the role of inflammasomes and IL-1 in these mice, since mutations in both A20 and Nlrp3 are associated with RA in patients. Also, IL-1 is a known target in RA.

In the beginning we worked closely with Geert van Loo. The expertise of Dirk Elewaut (UZGent) and Thirumala-Devi Kanneganti (St Jude Children’s Research Hospital, Memphis, USA) was also important. It was a pleasure to interact with all these people and arrive at a multidisciplinary approach to the problem. This made it possible to map out the role of A20 in inflammasome signaling and RA— biochemically, cell biologically and in vivo. Also, on a personal level, it was enriching to work with these talented people.

What are the next steps?
In our study, we showed at the genetic level that inflammasomes play an important role in RA. To demonstrate that A20 RA mice could be used for testing new RA therapies, we are presently doing proof-of-concept studies in which we inhibit the inflammasomes with (bio)pharmaceutical molecules before or after the development of RA. By doing this, we hope to make it easier for pharmaceutical to use this model and broaden the therapeutic options for RA patients.    

Back row from left to right: Rudi Beyaert, Dirk Elewaut and Geert van Loo; Middle row from left to right: Eveline Verheugen and Peggy Jacques; Row from left to right: Mohamed Lamkanfi, Nina Van Opdenbosch, Lieselotte Vande Walle and Amelie Fossoul
© VIB, 2014