An international team of researchers led by Professor Savvas Savvides, VIB-UGent Center for Inflammation Research, has unravelled a crucial aspect of the molecular basis of autoimmune and inflammatory diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis and Crohn's disease. Focusing on the immunomodulatory cytokine IL-23 they discovered that its pro-inflammatory activity, which underlies a wide range of inflammatory diseases, critically depends on structural activation of the cytokine by its receptor, IL-23R. The results of the study are published in the leading journal Immunity.
The prevalence of psoriasis, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis, has been rapidly expanding over the last few decades. The cytokine IL-23 - a specific type of immunomodulatory protein - plays a crucial role in these diseases. Consequently, IL-23 has become the focus of therapeutic strategies against such diseases.
Since the first description of IL-23 about a decade and a half ago, the structural and molecular basis for the mechanisms underlying the pro-inflammatory activity of IL-23 remained unclear. Professor Savvides and his team have now shed light on the unique way that IL-23 interacts with at least one of its receptors. In general, cytokines activate receptors. But surprisingly, in the current study, the opposite appeared to be true.
Professor Savvides explained: 'We were surprised to find that both IL-23 and its receptor change drastically to create an intimate cytokine-receptor interface. In this interface, the receptor uses a functional hotspot on IL-23, enabling it to recruit an essential co-receptor for pro-inflammatory signalling. The binding site of the co-receptor on IL-23 also emerged as an unexpected finding. What we have now discovered about the pro-inflammatory complex mediated by IL-23 appears to be a new paradigm in the field.'
The study was spearheaded by doctoral research fellow Yehudi Bloch and grew into a joint effort between research groups at the University of California (Davis, USA), Ghent University Hospital, and Professor Savvides' team at VIB and Ghent University. The researchers relied on integrative structural biology, combining methods to describe protein structures in atomic detail with complementary biochemical, biophysical, cellular and in vivo studies.
Professor Savvides said: 'These initial research milestones from our program on IL-23 will be the cornerstone for further research in our own labs and elsewhere. After all, many questions still remain unanswered. For instance: how does IL-23 bind with other possible co-receptors? Furthermore, our insights are expected to fuel the development of new therapeutic strategies against IL-23.'