• NOX4 protects against intestinal inflammation

    NCRC funded researchers at the Conway Institute, University College Dublin and the Centre for Paediatric Gastroenterology at Children’s Health Ireland, Crumlin have shown that NOX4 protects against intestinal inflammation.

    Inflammatory Bowel Diseases are characterised by the development of chronic inflammation within the digestive tract. Long term inflammation can lead to fibrosis or scarring within the intestine, which will cause narrowing and ultimately obstruction of the intestine. Surgery is required to remove intestinal blockages caused by scar tissue.

    In a newly published study, Dr Emily Stenke, Prof. Ulla Knaus and colleagues, investigated the role of NOX4 in the development of intestinal inflammation and fibrosis. NADPH oxidases are enzymes that generate oxidants (i.e. reactive oxygen species, a group of reactive and unstable molecules derived from oxygen). Reactive oxygen species play an essential role in many important biological processes. However, as they are highly reactive, a build-up of these species can lead to tissue damage and high levels are associated with several diseases. Conversely, loss-of-function mutations in certain NADPH oxidases are also associated with infectious and inflammatory diseases including chronic granulomatous disease and inflammatory bowel disease, demonstrating that there is a ‘sweet spot’ of physiological levels of reactive oxygen species required for human health.  NOX4 (NADPH oxidase 4) produces hydrogen peroxide and previous studies reported that NOX4 is critical for promoting the development of fibrosis in lung and liver but its putative role in intestinal fibrosis was unknown.

    In the study, they found that increased NOX4 expression is a feature of both inflammation and fibrosis in inflammatory bowel disease. Surprisingly, in mouse models of inflammatory bowel disease, loss of NOX4 did not influence fibrosis but was associated with more severe intestinal inflammation and increased tissue damage, suggesting that NOX4 may be protective in human intestinal inflammation.

    On publication of the study results, lead investigator Dr. Emily Stenke said: “Inflammatory bowel disease (IBD) affects both children and adults and a substantial number of patients have active disease despite available treatments. Understanding more about the factors that drive inflammation and fibrosis in IBD will bring new treatment possibilities. Our study shows for the first time that upregulation of NOX4, an enzyme producing physiological levels of the oxidant hydrogen peroxide, is a feature of both inflammation and fibrosis in IBD patients, while loss of NOX4 predisposed mice to severe intestinal inflammation. This suggests that NOX4 may be protective in human intestinal inflammation. Future research should tease out the protective mechanism and consider whether increasing levels of NOX4 or hydrogen peroxide would be a beneficial treatment strategy in patients with inflammatory IBD”.

    This research was published in Redox Biology, the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research Europe.

    The full publication can be found through the following link:

    Emily Stenke, Gabriella Aviello, Ashish Singh, Sean Martin, Des Winter, Brian Sweeney, Michael McDermott, Billy Bourke, Seamus Hussey, Ulla G Knaus. NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation. Redox Biology. Volume 37, October 2020, 101752.

    The research was supported by grants from the NCRC, the Health Research Board, and Science Foundation Ireland.

    Featured image: Haematoxylin & Eosin stained colon sections of wildtype and Nox4 deficient mice during the acute phase of chemical colitis.