NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice
Le Son Tran, Le Ying, Kimberley D’Costa, Georgie Wray‐McCann, Genevieve Kerr, L. Le, Cody C. Allison, Jonathan Ferrand, Hassan Chaudhry, Jack Emery, Amanda De Paoli, Nina Colon, Sarah J. Creed, Maria Kaparakis‐Liaskos, Julia Como, Jennifer K. Dowling, Priscilla Johanesen, Thomas A. Kufer, Jakob Skou Pedersen, Ashley Mansell, Dana J. Philpott, Kirstin Elgass, Helen E. Abud, Ueli Nachbur, Ben A. Croker, Seth L. Masters, Richard L. Ferrero
Abstract
The interleukin-1 family members, IL-1β and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1β processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori. Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori-induced pathology.