Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplantation Center, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.
Hepatology. 2013 Jul;58(1):351-62. doi: 10.1002/hep.26320. Epub 2013 May 15.
Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adaptor protein for inflammasome receptors, is essential for inducing caspase-1 activation and the consequent secretion of interleukin-1β (IL-1β), which is associated with local inflammation during liver ischemia/reperfusion injury (IRI). However, little is known about the mechanisms by which the ASC/caspase-1/IL-1β axis exerts its function in hepatic IRI. This study was designed to explore the functional roles and molecular mechanisms of ASC/caspase-1/IL-1β signaling in the regulation of inflammatory responses in vitro and in vivo. With a partial lobar liver warm ischemia (90 minutes) model, ASC-deficient and wild-type mice (C57BL/6) were sacrificed at 6 hours of reperfusion. Separate animal cohorts were treated with an anti-IL-1β antibody or control immunoglobulin G (10 mg/kg/day intraperitoneally). We found that ASC deficiency inhibited caspase-1/IL-1β signaling and led to protection against liver ischemia/reperfusion (IR) damage, local enhancement of antiapoptotic functions, and down-regulation of high mobility group box 1 (HMGB1)-mediated, toll-like receptor 4 (TLR4)-driven inflammation. Interestingly, the treatment of ASC-deficient mice with recombinant HMGB1 re-created liver IRI. Moreover, neutralization of IL-1β ameliorated the hepatocellular damage by inhibiting nuclear factor kappa B (NF-κB)/cyclooxygenase 2 signaling in IR-stressed livers. In parallel in vitro studies, the knockout of ASC in lipopolysaccharide-stimulated bone marrow-derived macrophages depressed HMGB1 activity via the p38 mitogen-activated protein kinase pathway and led to the inhibition of TLR4/NF-κB and ultimately the depression of proinflammatory cytokine programs.
ASC-mediated caspase-1/IL-1β signaling promotes HMGB1 to produce a TLR4-dependent inflammatory phenotype and leads to hepatocellular injury. Hence, ASC/caspase-1/IL-1β signaling mediates the inflammatory response by triggering HMGB1 induction in hepatic IRI. Our findings provide a rationale for a novel therapeutic strategy for managing liver injury due to IR.
凋亡相关斑点样蛋白包含半胱氨酸蛋白酶募集域 (ASC)，一种炎性体受体的衔接蛋白，对于诱导半胱天冬酶-1 激活和随后的白细胞介素-1β (IL-1β) 的分泌至关重要，白细胞介素-1β与肝缺血/再灌注损伤 (IRI) 期间的局部炎症有关。然而，ASC/caspase-1/IL-1β 轴发挥其在肝 IRI 中的功能的机制知之甚少。本研究旨在探讨 ASC/caspase-1/IL-1β 信号在体外和体内调节炎症反应中的功能作用和分子机制。在部分肝叶热缺血 (90 分钟) 模型中，在再灌注 6 小时时处死 ASC 缺陷型和野生型小鼠 (C57BL/6)。分别用抗 IL-1β 抗体或对照免疫球蛋白 G (10mg/kg/天腹腔内注射) 处理不同的动物组。我们发现 ASC 缺陷抑制 caspase-1/IL-1β 信号传导，并防止肝缺血/再灌注 (IR) 损伤、局部增强抗凋亡功能和下调高迁移率族蛋白 1 (HMGB1)-介导的、Toll 样受体 4 (TLR4) 驱动的炎症。有趣的是，用重组 HMGB1 处理 ASC 缺陷型小鼠会重新引起肝 IRI。此外，通过抑制核因子 kappa B (NF-κB)/环氧化酶 2 信号传导，中和 IL-1β 可改善 IR 应激肝脏中的肝细胞损伤。在平行的体外研究中，在脂多糖刺激的骨髓来源的巨噬细胞中敲除 ASC 通过丝裂原活化蛋白激酶 p38 通路抑制 HMGB1 活性，并导致 TLR4/NF-κB 的抑制，最终抑制促炎细胞因子程序。
ASC 介导的 caspase-1/IL-1β 信号传导促进 HMGB1 产生 TLR4 依赖性炎症表型并导致肝细胞损伤。因此，ASC/caspase-1/IL-1β 信号通过触发肝 IRI 中 HMGB1 的诱导来介导炎症反应。我们的研究结果为管理 IR 引起的肝损伤提供了一种新的治疗策略的依据。
