Cell-type specific role of non-canonical inflammasome during LPS septic shock

Abstract Cytosolic sensing of LPS through caspase-11 is the key step of non-canonical inflammasome activation and innate immune defense against Gram-negative bacterial infections. Upon LPS sensing, caspase-11 induces GSDMD-mediated pore formation in the plasma membrane, followed by maturation and secretion of caspase-1 and pro-inflammatory cytokines (IL1band IL18). Excessive pore formation on the membrane leads to pyroptotic death of cell and release of intracellular proteins; many of which exacerbate the immune responses to infection, leading to cytokine storm, tissue damage, organ failure, and death. Caspase-11 sensing of LPS occurs in various cell-types, however the contribution of these cell-types to non-canonical inflammasome mediated pyroptosis, cytokine release, and lethality during LPS septic shock is poorly understood. To understand the cell type-specific role of caspase-11 during LPS septic shock, caspase-11 was conditionally deleted in multiple cell-types including macrophages by utilizing caspase-11 floxed mice and several appropriate Cre strains. The conditional KOs of caspase-11 were subjected to LPS challenge and various responses were assessed. Our in vivostudies showed cell-type specific contribution of caspase-11 to intracellular LPS-induced responses such as gasdermin D activation and lethality. Particularly, myeloid cell-intrinsic expression of caspase-11 is required for pathological manifestations of intracellular LPS sensing. Overall, our findings provide new insights into the cell type-specific role of cytosolic LPS sensing.