Caspase-4: A Therapeutic Target for Peptic Ulcer Disease.

Peptic ulcers are caused by the interaction between bacterial and host factors. This study demonstrates enhanced expression of caspase-4 in peptic ulcer patient biopsies, indicating that pyroptosis and noncanonical inflammasome activity may be processes involved in peptic ulcer disease. We show that primary murine macrophages infected with upregulate caspase-11 (the ortholog of human caspase-4), activate caspase-1, and secrete IL-1β. We demonstrate that misoprostol (a stable PGE analogue) decreased IL-1β secretion and delayed lethality in vivo in a murine peritonitis model. PGE was shown to inhibit caspase-11-driven pyroptosis and IL-1β secretion in macrophages. Overall, we provide evidence for a pathological role of caspase-4/11 in peptic ulcer disease and propose that targeting caspase-4 or inhibiting pyroptosis may have therapeutic potential in the management of peptic ulcers.