The check engine light is a signal from a car’s engine computer that something is wrong. The light could be a minor issue or it could mean something more serious. Nonetheless, it’s an indicator that something is wrong and an issue needs to be repaired. When functioning correctly, our immune system is like the check engine light. However, in some cases such as inflammatory bowel disease (IBD), the immune system responds incorrectly to environmental triggers. Now, researchers at KU Leuven and Seoul National University report they have developed a method that instructs immune system cells to help repair damaged tissues in the intestine. This method paves the way for more effective treatments of IBD.
Their method and findings were published in the journal Gut in a paper titled, “Prostaglandin E2 receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation.”
IBD is a term for two conditions (Crohn’s disease and ulcerative colitis) that are characterized by chronic inflammation of the gastrointestinal (GI) tract. Prolonged inflammation results in damage to the GI tract.
“Dysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease,” wrote the researchers. “Intestinal macrophages are vital in the process of inflammation resolution, but the mechanisms underlying their mucosal healing capacity remain elusive.”
When the immune system isn’t functioning correctly in conditions such as IBD, it attacks the tissues that line the gut. Since the origin of IBD is unknown, treatments often focus on reducing the immune response in order to limit inflammation and the resulting symptoms. However, this also hinders those parts of the immune system involved in repairing the damaged intestine.
“Our idea is that the migration of macrophages to the damaged tissue in IBD is essential to stimulate its recovery,” explained Gianluca Matteoli, PhD an immunologist at the Translational Research Center for Gastrointestinal Disorders (TARGID) KU Leuven and lead author of the research. Matteoli’s team and Seung Hyeok Seok, PhD, a professor at Seoul National University, set out to test this theory.
When the researchers looked at macrophages in the intestines of a handful of people with IBD, a sub-group of cells able to respond to prostaglandin E2 (PGE2) stood out.
“If the patients had acute disease, they had a lower amount of these beneficial cells, and if they went into remission, then amounts of macrophages went up. This suggests that they are part of the reparative process,” Matteoli explained.
The researchers used a mouse model of ulcerative colitis to investigate further. The number of macrophages sensitive to the prostaglandin was lower in the model than in healthy mice, but if PGE2 levels were increased, the few sensitive macrophages present responded, releasing a substance that in turn stimulated tissue regeneration.
If the PGE2 receptors on the macrophages were knocked out, making them unable to respond to the prostaglandin, the level of tissue regeneration dropped. But it could be restored by getting the macrophages to swallow a liposome containing a substance able to trigger the release of the repair stimulating agent.
“We already knew that prostaglandins were important for inducing proliferation of tissue cells, but this study shows that they are also important for controlling the inflammatory effect, so moving the body from the acute stage where inflammation dominates to the reparative stage,” Matteoli noted.
“This is one of the first times it has been used to produce a beneficial, therapeutic effect,” said Seok. However, a lot of work will be needed before it can be used in patients.
Looking toward the future, the researchers will observe macrophages at different stages of IBD. “We want to identify other factors that trip the switch that turns macrophages from inflammatory cells to non-inflammatory cells,” added Matteoli. “Then, using the liposome technology that Seok has developed, these could be used to target the macrophages and so produce very precise drugs.”
“TGER4+ intestinal macrophages are essential for supporting the intestinal stem cell niche and regeneration of the injured epithelium,” the researchers concluded. “Our results pave the way for the development of a new class of therapeutic targets to promote macrophage healing functions and favor remission in patients with IBD.”
