Tran LS, Ying L, D'Costa K, Wray-McCann G, Kerr G, Le L, Allison CC, Ferrand J, Chaudhry H, Emery J, De Paoli A, Colon N, Creed S, Kaparakis-Liaskos M, Como J, Dowling JK, Johanesen PA, Kufer TA, Pedersen JS, Mansell A, Philpott DJ, Elgass KD, Abud HE, Nachbur U, Croker BA, Masters SL, Ferrero RL.
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.