The canonical (caspase-1) and noncanonical (caspase-4/5/11) inflammasomes both cleave gasdermin D (GSDMD) to induce pyroptosis.Whereas caspase-l processes IL-1β and IL-18 for maturation, no cytokine target has been firmly established for LPS-activated caspase-4/5/11. Here we show that activated human caspase-4, but not mouse caspase-ll, directly and efficiently processes IL-18 in vitro and during bacterial infections, which mainly occurs in epithelial cells. Crystal structure of the caspase-4/pro-IL-18 complex reveals a binary substrate-recognition mechanism, including a unique exosite that binds to a specific structure formed jointly by the propeptide and post-cleavage-site sequences in pro-IL-18. In caspase-ll,a structural deviation around the exosite underlies its inability to target pro-IL-18,which can be restored by rationally designed mutations. The structure of pro-IL-18 features autoinhibitory interactions between the propeptide and the post-cleavage-site region, preventing recognition by the IL-18Ra receptor. Meanwhile,we also find that GSDMD activation by LPS-ligated caspase-4/llspecifically in brain endothelial cells, but not TLR4-induced cytokines, mediates BBB (blood brain barrier) breakdown in response to circulating LPS or during LPS-induced sepsis. Electron microscopy re- cords ultrastructural changes in the disrupted BBB, including pyroptotic endothelia, abnormal appearance of tight junctions, and vasculature detachment from basement membrane. Delivery of active GSDMD into brain endothelial cells bypasses LPS stimulation and opens the BBB. In CASP4-humanized mice, Gram-negative Klebsiella pneumoniae infection disrupts the BBB, which is blocked by a GSDMD-neutralizing nanobody expressed in brain endothelial cells. These findings together shift the paradigm in the understanding of noncanonical-inflam-masome-mediated antibacterial defenses and sepsis.