Immune Cell Circuit Restores Barrier Function in IBD

Scientists have discovered a new protective communication circuit between specialized immune cells in the intestines, a circuit that may be therapeutically targeted to improve inflammatory bowel disease outcomes, according to a recent study published in the Proceedings of the National Academy of Sciences.

Inflammatory bowel disease (IBD), a group of chronic diseases affecting the intestines, impacts an estimated three million people in the U.S., according to a recent report from the Centers for Disease Control and Prevention.

IBD progression is driven by the breakdown of immune regulation and epithelial cell barrier function, causing increased inflammation within the intestines. Many types of cells in the intestine contribute to this inflammation, including eosinophils, a type of white blood cell that infiltrate the intestinal mucosa during inflammation and recovery. However, the role of eosinophils in determining disease outcomes has remained unclear.

In the current study, the scientists used RNA-seq techniques  and mouse models of IBD to identify gene expression patterns in eosinophils isolated from healthy and inflamed colon tissue in mice.

In eosinophils from mice with inflamed colon tissue, they discovered increased expression of the PTGS2 gene, which encodes the enzyme cyclooxygenase-2 (COX-2). COX-2 also produces molecules that regulate and impact immune system activity.

Next, the scientists used genetic engineering techniques to remove COX-2 from these eosinophils, which increased inflammation in the mice and induced early onset of IBD and more severe disease.

Most importantly, the scientists discovered a protective communication circuit involving eosinophils and a type of tissue-resident immune cell in the intestines, called type 3 innate lymphoid cells (ILC3s), in which eosinophils and ILC3s communicate to restrain intestinal inflammation.

“IBD represents an imbalance of immune promoting and immune regulating factors, with overactivity of proinflammatory pathways leading to the hallmark symptoms and bowel damage observed in the condition. This protective circuit might provide a counterbalance to the chronically disrupted immune activity present in IBD,” said Keith Summa, ‘16 MD, ‘13 PhD, assistant professor of Medicine in the Division of Gastroenterology and Hepatology, who was a co-author of the study.

The findings clarify the role of eosinophils in chronic IBD-related immune dysregulation, which can help inform future treatment strategies that could strengthen the intestinal barrier and prevent inflammation.

“In the experimental models and context of our studies, it appears that eosinophils help to restrain or limit the inflammatory response in the colon by generating signaling molecules that impact other immune cells to turn down the inflammatory response. This may help to improve treatment strategies for IBD by providing a new target: medications or techniques to augment this protective circuit may strengthen the intestinal barrier and protect against the development or progression of inflammation in IBD,” said Yingzi Cong, PhD, the Stanley Gradowski Professor of Gastroenterology and a professor of Microbiology-Immunology and of Pathology, who was a co-author of the study.

The scientists said they next aim to identify the factors that promote the activity and regulation of the eosinophil-ILC3 circuit.

“If we can understand the factors that turn this circuit on and turn it off, we will be better positioned to identify situations and factors that may contribute to worsening inflammation in IBD as well as specific treatment strategies to impact IBD progression by enhancing this protective circuit,” the authors said.

Cong is also a member of the Center of Human Immunobiology.

This work was supported by the National Institute of Health (NIH) DK121330 and AA030735, DK056338 DK121330 and AI145108; the Mayo Foundation grant; and the Trauma Research and Combat Casualty Care Collaborative (TRC4) Early Career Mentored Research Awards.