Molecular determinants of noncanonical inflammasome activation by LPS

Abstract

Abstract Septic shock is the leading cause of morbidity and mortality in intensive care units worldwide. Gram-negative bacteria constitute one of the most common causes of sepsis that results in high fatality by initiating an excessive and uncontrolled host inflammatory response. At the epicenter of this response is the innate immune detection of lipopolysaccharides (LPS). In addition to TLR4 recognition of LPS, recent studies revealed a new LPS sensing mechanism in the cytosol. Inflammatory caspases, such as caspase-11, detect LPS to execute pyroptosis, an inflammatory form of cell death, and caspase-1 activation. A prerequisite for the activation of noncanonical inflammasome is the transcriptional induction of caspase-11, which is mediated by TLR4-TRIF, type I interferon, and complement signaling. Additionally, guanylate binding proteins (GBPs), interferon regulatory factor 1, and IRGB10 orchestrate the release of LPS from the vacuolar bacterial pathogens into the cytosol. While the host factors involved in LPS activation of caspase-11 are fairly characterized, the role of bacterial factors in this process is not clear. Our new findings from this study delineate the bacterial components necessary for the optimal engagement of the cytosolic LPS sensing pathway and eliciting noncanonical inflammasome responses.