While human macrophages employ a multifactorial inflammasome response to Salmonella infection, human intestinal epithelial cells (IECs) rely on a single inflammasome, the caspase-4/5 inflammasome, during Salmonella infection. In human macrophages, Salmonella infection induces NAIP/NLRC4, NLRP3, and caspase-4/5 inflammasome responses, facilitating IL-1 cytokine release, pyroptosis, and ultimately restriction of bacterial replication. In contrast, in human IECs undergo a caspase-4-dependent, NAIP/NLRC4- and NLRP3-independent inflammasome response to Salmonella infection.