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Growth factor deficiency identified in TNF-induced inflammatory bowel disease

A Cornell research team has identified a new target for treatment in inflammatory bowel disease. (Image: TNF-driven epithelial inflammation; Dr. Lei Zhou/Sonnenberg Lab)

Inflammatory bowel disease (IBD) is a chronic condition characterized by various abnormal immune responses, resulting in inflammation of the gastrointestinal tract. Victims of IBD have a greatly reduced quality of life, often suffering from episodes of diarrhea, fever, and abdominal pain. From 1999 to 2015, the prevalence of IBD increased 55%, from 2 million U.S. adults suffering from the condition, to an estimated 3 million.

Tumor necrosis factor (TNF) has long been known to be a major contributor to IBD. Excessive TNF production in the gastrointestinal tract leads to cell death, causing inflammation. Backed by a large body of research, current therapeutics focus on reducing TNF production have shown to be most effective in treating IBD, but new research shows a new possible therapeutic target.

A research group out of Weill Medical College of Cornell University has found that ILC3 cells, a certain innate lympoid cell, produces HB-EGF, which is a growth factor functions to protect the intestinal epithelium from cell death.

Senior author Dr. Gregory Sonnenberg, told Weill Cornell Medicine Newsroom, “We’ve discovered a new cellular pathway that is essential to protect against gut inflammation. This discovery could lead to a better understanding of IBD pathogenesis and new strategies to treat this disease.”

He went on to add, “Identifying the significance of this pathway is a good first step, and we’re now thinking about how we might manipulate this pathway to benefit IBD patients.”

The study revealed a deficiency in HB-EGF producing ILC3 cells in IBD patients. Additionally, the team demonstrated that compared to controls, ILC3-deficient mice showed significantly larger amounts of intestinal damage, which was observed due to decreases in colon length, increases in weight loss, and structural disruptions of the GI tract.

These findings provide an expanded explanation for the intestinal inflammation resulting from the overproduction of TNF.

First author, Dr. Lei Zhou, shared his thoughts on the discovery, stating, “It will be important to delineate the exact cellular and molecular mechanisms by which this novel pathway coordinates intestinal health, inflammation and cancer before moving forward with manipulating it as a therapeutic strategy.”

The study was published in Nature Immunology, on January 31st, 2022.

Abstract. Tumor necrosis factor (TNF) drives chronic inflammation and cell death in the intestine, and blocking TNF is a therapeutic approach in inflammatory bowel disease (IBD). Despite this knowledge, the pathways that protect the intestine from TNF are incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3s) protect the intestinal epithelium from TNF-induced cell death. This occurs independent of interleukin-22 (IL-22), and we identify that ILC3s are a dominant source of heparin-binding epidermal growth factor–like growth factor (HB-EGF). ILC3s produce HB-EGF in response to prostaglandin E2 (PGE2) and engagement of the EP2 receptor. Mice lacking ILC3-derived HB-EGF exhibit increased susceptibility to TNF-mediated epithelial cell death and experimental intestinal inflammation. Finally, human ILC3s produce HB-EGF and are reduced from the inflamed intestine. These results define an essential role for ILC3-derived HB-EGF in protecting the intestine from TNF and indicate that disruption of this pathway contributes to IBD.

Zhou, L., Zhou, W., Joseph, A.M. et al. Group 3 innate lymphoid cells produce the growth factor HB-EGF to protect the intestine from TNF-mediated inflammation. Nat Immunol (2022).

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