Scientists at Weill Cornell Medicine have found a new connection between two important pathways that control the immune system in mammals. This discovery has implications for our understanding of chronic inflammatory bowel diseases (IBD), which greatly affect the health and quality of life of over 2 million people in the United States.More than 2 million people in the United States benefit from health and quality of life. The immune system has various pathways to protect the body from infection, but an overactive response can lead to autoimmune diseases such as IBD, psoriasis, rheumatoid arthritis, and multiple sclerosis. Interleukin-23 (IL-23) is an immune factor that fights infections but is also involved in these inflammatory diseases. However, it was previously unclear why IL-23 could be beneficial in some cases and contribute to chronic disease in others. In a study published on June 12 in Nature, the team discovered that IL-23 has an effect on ILC3s, which are immune cells that play a crucial role in protecting mucosal tissues like the intestines and lungs. When IL-23 acts on ILC3s, it leads to an increase in the activity of CTLA-4, which is a key factor in regulating the immune system to prevent it from attacking the body and beneficial gut bacteria. This interaction is important for balancing the pro-inflammatory effects of IL-23 to keep the gut healthy, but it is not working properly in IBD.
The research shows that ILC3s are a crucial connection between the powerful inflammatory response driven by IL-23 and the checkpoints for regulating the immune system in the intestine. It also gives insight into how to use this information to help. The discovery of a new pathway to combat cancer and reduce the effects of cancer immunotherapy was surprising, according to senior author Dr. Gregory Sonnenberg. This connection between two major immune pathways that regulate health, immunity, and inflammation was unexpected. Dr. Sonnenberg, who is the Henry R. Erle, M.D.-Roberts Family Professor of Medicine and head of basic research in the Division of Gastroenterology & Hepatology at Weill Cornell Medicine, expressed his surprise at the finding. Previous research on CTLA-4 had primarily focused on T cells, but the discovery revealed that it selectively affects a different type of immune cell.IL-23 upregulates ILC3s, indicating the need for a broader consideration of these pathways in the development of more targeted treatments.
When Inflammation is Out of Control
“IL-23 typically protects tissue in the gut, but in chronic inflammatory diseases, it becomes a significant contributor to tissue pathology, which led us to investigate further,” explained Dr. Anees Ahmed, the lead author of the study and a postdoctoral researcher.
The researchers utilized single-cell RNA sequencing to examine the impact of IL-23 on various immune cell types.The researchers conducted a study on the healthy intestine and found that IL-23 activates the CTLA-4 pathway in ILC3s. They discovered that blocking the CTLA-4 pathway in these cells led to severe inflammation in the intestine. To confirm their findings in humans, the researchers used deidentified samples from people with IBD and healthy individuals. This helped them quickly validate their results in mice and apply them to patients with IBD. Collaboration with other researchers further confirmed their findings in patients.Dr. Robbyn Sockolow, a clinical pediatrics professor and head of the Division of Pediatric Gastroenterology, Hepatology and Nutrition at Weill Cornell Medicine, as well as a pediatric gastroenterologist at NewYork-Presbyterian Komansky Children’s Hospital and Center for Advanced Digestive Care, has discovered evidence of a new immunologic pathway in the healthy human intestine. However, this pathway becomes impaired in the inflamed intestine of patients with inflammatory bowel disease (IBD). Dr. Sockolow believes that this finding may offer a new explanation for why IL-23 becomes a driver of intestinal inflammation in human IBD. The research also indicates that this process could be used to combat cancer and could provide an explanation for why individuals undergoing specific immunotherapy medications often encounter gut inflammation as a side effect. CTLA-4 blockade immunotherapy drugs are utilized to release the brakes on the immune system, enabling it to battle cancer. These recent findings propose that the presence of CTLA-4 on ILC3 cells and other similar innate or innate-like lymphocytes should be taken into account when fighting cancer. Additionally, it suggests that inhibiting CTLA-4 on ILC3s could result in severe gut inflammation, leading to patient discomfort. The researchers discovered that blocking a specific immune cell could help improve cancer treatment. This finding may lead to the development of more targeted treatments in the future, which could potentially reduce inflammation in the gut. However, more research is necessary before this discovery can be translated into new treatments. Dr. Ahmed believes that in the future, it may be possible to selectively block certain immune cells to fight cancer while also protecting the gut from inflammation. This breakthrough could have long-term implications for developing treatments for autoimmune diseases.
IL-23 is the target of certain drugs that already exist, and there is potential for developing next-generation treatments that don’t completely block IL-23. This is because IL-23 is still necessary for fighting infections, so the focus would be on controlling the underlying mechanisms of IL-23-driven chronic inflammatory diseases, according to Dr. Sonnenberg.
