NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection

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 well 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 epithelial cells to the mucosal pathogens, Helicobacter pylori and Pseudomonas aeruginosa. We show that IL-18 is important in protecting against pre-neoplastic changes induced by gastric H. pylori infection in vivo. NOD1 mediates IL-18 processing via homotypic CARD-CARD interactions with caspase-1, and independently of canonical inflammasome proteins (NLRP3, ASC). These findings reveal an unanticipated role for NOD1 in the formation of bioactive IL-18, thereby underlining the differences in inflammasome functions between haematopoietic and non-haematopoietic cells.