New microbiome-based evidence suggests a two-drug combination, a blockade of both IL-22 and IL-1R, may treat inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis. This team studied “upstream cues” of microbial interactions with intestinal cells. They report that IL-22 and IL-1R can trigger “a chain reaction” that drives an excessive inflammatory response.
“The pathogenic role that IL-22 appears to play in inflammatory responses—due to its synergy with IL-1R signaling—had not been made clear previously,” says corresponding author Chandrashekhar Pasare, DVM, PhD, Cincinnati Children’s Division of Immunobiology and co-director, Center for Inflammation and Tolerance.
“We believe this may help explain why past treatments for IBD that focused only on inhibiting IL-1β activity had mixed results. We believe that a combined blockade of both IL-22 and IL-1R could serve as a more promising treatment for IBD,” he added.
This study, led by researchers at Cincinnati Children’s, was published last week in the Journal of Experimental Medicine. Co-first authors were Garrett Overcast, PhD, and Hannah Meibers, BS.
An estimated three million people in U.S. alone have IBD. A global study, published in The Lancet, found that in 2017 there were 6.8 million cases around the world. The global market for IBD was estimated to be worth over 20 billion last year. Almost 3,000 clinical trials are currently looking at this disease.
This team analyzed how immune cells located in the lining of the intestine detect and respond to microbes and relay important signals to gut epithelial cells. When the signaling networks between immune cells and epithelial cells function correctly, they say, the immune system can live in harmony with friendly bacteria residing in the gut.
But when microbe-to-cell signals get scrambled—by genetic mutations or other causes such as damage to the intestinal epithelium—the immune system can either fail to react or can over-react, which can lead to IBD.
According to this research, microbes are detected by cells of the immune system located in the intestines. These immune cells deliver signals to the protein IL-1, which increases levels of the protein IL-22. This protein begins acting in concert with IL-1 to activate the IL-1 receptor (IL-1R) expressed on intestinal epithelial cells. Activation of IL-1R induces ROS gene activity in addition to other genes that recruit inflammatory cells to the tissue. This chain reaction drives an excessive inflammatory response that can damage the intestine, the researchers say.
Some monoclonal antibodies that can inhibit IL-22 or IL-1R have been evaluated in clinical trials for various autoimmune conditions. This research team is interested in exploring whether existing products can be safely used in combination therapy or whether developing new treatments that target the two pathways would be more effective.