Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Lin Jiang Road, Chongqing, 400010, China.
Department of Pathology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Cell Commun Signal. 2024 Nov 20;22(1):556. doi: 10.1186/s12964-024-01944-9.
Absent in melanoma 2 (AIM2) inflammasome-dependent pyroptosis and neutrophil extracellular traps (NETs) have been implicated in chronic liver disease (CLD). However, the specific intrahepatic cell type that undergoes AIM2 inflammasome-dependent pyroptosis and how their interaction augments hepatic inflammation/fibrosis remains unclear.
The expression and correlation of AIM2 inflammasome-dependent pyroptosis-related indicators and NETs were analyzed in biopsy tissue and blood specimens from chronic hepatitis patients (CHs). Cell-based experiments were conducted to investigate their interaction. In vitro and in vivo experiments were used to analyze their effects on the progression of hepatic inflammation/fibrosis as well as their clinical importance.
Elevated levels of AIM2 inflammasome-dependent pyroptosis indicators and NETs were detected in biopsy tissue and blood specimens. Circulating NETs were positively correlated with pyroptosis-related indicators, and both were related with disease severity. Confocal imaging revealed that AIM2 was mainly localized to hepatic macrophages, indicating that hepatic macrophages were the major cell type that underwent pyroptosis. NETs were directly engulfed by macrophages and then stimulated AIM2 inflammasome-dependent macrophage pyroptosis in vitro, which amplified the activation of hepatic stellate cells (HSCs) and increased collagen deposition. Administration of the NETs degradation agent DNase I or the AIM2 inflammasome activation inhibitor ODN A151 effectively alleviated chronic liver inflammation/fibrosis progression in vivo.
NETs-induced AIM2 inflammasome-dependent pyroptosis in macrophages facilitates liver inflammation/fibrosis progression. The identified NET-AIM2 inflammasome cascade could serve as a novel therapeutic target for hepatic inflammation/fibrosis progression.
在黑色素瘤 2（AIM2）炎性小体依赖性细胞焦亡和中性粒细胞胞外诱捕网（NETs）与慢性肝病（CLD）有关。然而，经历 AIM2 炎性小体依赖性细胞焦亡的特定肝内细胞类型以及它们的相互作用如何增强肝炎症/纤维化仍然不清楚。
分析慢性肝炎患者（CHs）活检组织和血液标本中 AIM2 炎性小体依赖性细胞焦亡相关指标和 NETs 的表达和相关性。进行基于细胞的实验以研究它们的相互作用。进行体外和体内实验以分析它们对肝炎症/纤维化进展的影响及其临床意义。
在活检组织和血液标本中检测到 AIM2 炎性小体依赖性细胞焦亡指标和 NETs 的水平升高。循环 NETs 与细胞焦亡相关指标呈正相关，两者均与疾病严重程度相关。共聚焦成像显示 AIM2 主要定位于肝巨噬细胞，表明肝巨噬细胞是经历细胞焦亡的主要细胞类型。NETs 被巨噬细胞直接吞噬，然后在体外刺激 AIM2 炎性小体依赖性巨噬细胞细胞焦亡，放大肝星状细胞（HSCs）的激活并增加胶原沉积。NETs 降解剂 DNase I 或 AIM2 炎性小体激活抑制剂 ODN A151 的给药在体内有效缓解慢性肝炎症/纤维化的进展。
NETs 诱导巨噬细胞中 AIM2 炎性小体依赖性细胞焦亡促进肝炎症/纤维化的进展。鉴定的 NET-AIM2 炎性小体级联反应可以作为肝炎症/纤维化进展的新治疗靶点。
