Scientists Determine Structure of Major Cytokine Involved in MS Inflammation
A global collaboration of researchers led by Belgium’s Flanders Institute for Biotechnology has determined the structure of the pro-inflammatory cytokine IL-23 and its receptor IL-23R, which could be potential targets for treating multiple sclerosis (MS) and other autoimmune diseases.
Their study, “Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1,” appeared in the journal Immunity.
IL-23 is a pro-inflammatory protein that plays a crucial role in inflammatory diseases including MS, rheumatoid arthritis, psoriasis and inflammatory bowel diseases. It functions by binding to IL-23R, which is embedded in the outer membrane of several types of immune cells. When IL-23 interacts with IL-23R at the cell surface, it triggers a series of chemical signals inside the cell that promote inflammation.
Although the regulatory functions and disease-related context of IL-23 is well-known, little information exists on the structure of this protein. For this reason, researchers set out to determine the structure of IL-23.
Researchers were able to map out the structure of IL-23 interacting with its receptor IL-23R based on biochemical and biophysical experiments. By determining the structure of the IL-23:IL-23R complex, scientists discovered that IL-23 binds IL-23R exclusively through the N-terminal immunoglobulin domain.
Interestingly, researchers discovered that upon binding of IL-23 to IL-23R, there was a partial restructuring of a subunit of IL-23 called the IL-23p19 subunit. Normally, cytokines tend to activate their receptors, but in this case, the opposite was also true.
The change in the structure of IL-23 allowed the IL-23R to restrain another subunit of IL-23 called the p40 subunit, which then allowed IL-23 to have a high-affinity interaction with another receptor, IL-12Rβ1. Activation of both IL-23R and IL-12Rβ1 led to pro-inflammatory signaling.
“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 signaling,” Savvas Savvides, lead author of the paper, said in a press release.
“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,” added Savvides.
These findings regarding the structure of IL-23 could represent the next treatment strategy for autoimmune diseases.
“Strategies addressing specifically the obligate IL-23:IL-23R binary complex or the functional hotspot…in IL-23p19 may offer additional avenues to address the broad spectrum of diseases linked to IL-23,” the study said.