Cell 180, 50–63 (2020)

The enteric nervous system forms an extensive network of intimate interactions with mucosal epithelial cells and tissue-resident immune cells. In Cell, Jarret et al. report that enteric neurons constitutively express interleukin (IL)-18 through a caspase-1-independent pathway. Importantly, neuronal IL-18 is non-redundant in providing protection against invasive Salmonella typhimurium (S.t.). Mice with a specific deletion of Il18 in enteric neurons, generated using Hand2 promoter-driven Cre recombinase, are more susceptible to S.t. infection, whereas specific loss of IL-18 in epithelial or hematopoietic cells is dispensable for S.t. control. Loss of neuronal IL-18 specifically affected goblet cell production of antimicrobial peptides in the colon and bacterial exclusion from the inner mucus layer; however, this effect is indirect, and it remains unclear which cells are the relevant IL-18R+ responding cells. Thus, neuronal IL-18 is essential for colonic barrier protection.