TRIF signaling is required for caspase-11-dependent immune responses and lethality in sepsis

• Main Authors: Yiting Tang (Author), Rui Zhang (Author), Qianqian Xue (Author), Ran Meng (Author), Xiangyu Wang (Author), Yanliang Yang (Author), Lingli Xie (Author), Xianzhong Xiao (Author), Timothy R. Billiar (Author), Ben Lu (Author)
• Format: Book
• Published: BMC, 2018-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Abstract Background Caspase-11, a cytosolic receptor of bacterial endotoxin (lipopolysaccharide: LPS), mediates immune responses and lethality in endotoxemia and experimental sepsis. However, the upstream pathways that regulate caspase-11 activation in endotoxemia and sepsis are not fully understood. The aim of this study is to test whether TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling is critical for caspase-11-dependent immune responses and lethality in endotoxemia. Methods Mice of indicated genotypes were subjected to endotoxemia or cecum ligation and puncture (CLP) and monitored daily by signs of a moribund state for lethality. Serum interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor (TNF) were measured by ELISA. Data were analyzed by using student's t-test or one-way ANOVA followed by post-hoc Bonferroni test. Survival data were analyzed by using the log-rank test. Results Blockade of type 1 interferon signaling or genetic deletion of TRIF or guanylate-binding proteins (GBPs) prevented caspase-11-dependent immune responses, organ injury and lethality in endotoxemia and experimental sepsis. In vitro, deletion of GBPs blocked cytosolic LPS-induced caspase-11 activation in mouse macrophages. Conclusions These findings demonstrate that TRIF signaling is required for caspase-11-dependent immune responses and lethality in endotoxemia and sepsis, and provide novel mechanistic insights into how LPS induces caspase-11 activation during bacterial infection.

Item Description

10.1186/s10020-018-0065-y
1076-1551
1528-3658