Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, 410000, People's Republic of China.
Department of Hematology and Key Laboratory of Non-resolving Inflammation and Cancer of Hunan Province, The 3rd Xiangya Hospital, Central South University, Changsha, 410000, People's Republic of China.
Mol Med. 2018 Dec 27;24(1):66. doi: 10.1186/s10020-018-0065-y.
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.
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.
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.
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.
Caspase-11 是细菌内毒素（脂多糖：LPS）的细胞质受体，它介导内毒素血症和实验性败血症中的免疫反应和致死作用。然而，调控内毒素血症和败血症中 caspase-11 激活的上游途径尚不完全清楚。本研究旨在测试 TIR 结构域包含衔接子诱导干扰素-β（TRIF）信号是否对 caspase-11 依赖性免疫反应和内毒素血症中的致死作用至关重要。
用指示基因型的小鼠进行内毒素血症或盲肠结扎和穿刺（CLP），并通过濒死状态的迹象每天监测其死亡率。通过 ELISA 测定血清白细胞介素（IL）-1α、IL-1β、IL-6 和肿瘤坏死因子（TNF）。使用学生 t 检验或单因素方差分析（ANOVA），并进行事后 Bonferroni 检验分析数据。使用对数秩检验分析生存数据。
阻断 I 型干扰素信号或 TRIF 或鸟苷酸结合蛋白（GBPs）的基因缺失可防止内毒素血症和实验性败血症中 caspase-11 依赖性免疫反应、器官损伤和致死作用。在体外，GBPs 的缺失可阻断细胞质 LPS 诱导的小鼠巨噬细胞中 caspase-11 的激活。
这些发现表明，TRIF 信号对于内毒素血症和败血症中 caspase-11 依赖性免疫反应和致死作用是必需的，并为 LPS 在细菌感染过程中如何诱导 caspase-11 激活提供了新的机制见解。
