Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury.
Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury.
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损伤相关分子模式激活的中性粒细胞胞外陷阱加剧了无菌性炎症性肝损伤。
DOI：
10.1002/hep.27841
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发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Tsung A
中科院分区：
文献类型：
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作者：
Huang H;Tohme S;Al-Khafaji AB;Tai S;Loughran P;Chen L;Wang S;Kim J;Billiar T;Wang Y;Tsung A
先天免疫在对肝脏缺血/再灌注（I/R）损伤等无菌炎症的反应中发挥着至关重要的作用。肝缺血再灌注损伤的启动会导致损伤相关分子模式 (DAMP) 的释放，从而通过模式识别受体触发先天免疫和炎症级联反应。缺血再灌注后，中性粒细胞被募集至肝脏，导致器官损伤、先天免疫和炎症反应。最近发现中性粒细胞胞外陷阱（NET）的形成是对各种刺激的反应。然而，NETs 在肝 I/R 损伤过程中的作用仍不清楚。我们发现 NETs 在体内缺血肝叶的血窦中形成。与对照小鼠相比，这与 NET 标记物、髓过氧化物酶 (MPO)-DNA 复合物的血清水平和瓜氨酸组蛋白 H3 的组织水平增加有关。肽基精氨酸脱亚胺酶 (PAD) 4 抑制剂或 DNase I 治疗可显着保护肝细胞并减少肝 I/R 后的炎症，这一点可通过抑制 NET 形成来证明，这表明 NET 在肝 I/R 损伤中的病理生理学作用。在体外，NETs 会增加肝细胞死亡并诱导库普弗细胞释放促炎细胞因子。受损肝细胞释放的 DAMP（例如 HMGB1 和组蛋白）通过 Toll 样受体 (TLR4) 和 TLR9-MyD88 信号通路刺激 NET 形成。小鼠中性粒细胞耗竭后，TLR4 敲除 (KO) 或 TLR9 KO 中性粒细胞的过继转移可显着防止肝 I/R 损伤，同时 NET 形成显着减少。此外，我们发现 PAD4 抑制剂或 DNase I 抑制 NET 形成可减少 HMGB1 和组蛋白介导的肝 I/R 损伤。肝脏 I/R 期间释放的 DAMP 通过 TLR 信号通路促进 NET 形成。 NETs 的发展随后会加剧器官损伤并在肝脏 I/R 过程中引发炎症反应。
Innate immunity plays a crucial role in the response to sterile inflammation such as liver ischemia/reperfusion (I/R) injury. The initiation of liver I/R injury results in the release of damage associated molecular patterns (DAMPs), which trigger innate immune and inflammatory cascade via pattern recognition receptors. Neutrophils are recruited to the liver after I/R and contribute to the organ damage, innate immune and inflammatory responses. Formation of neutrophil extracellular trap (NET) has been recently found in response to various stimuli. However, the role of NETs during liver I/R injury remains unknown. We show that NETs form in the sinusoids of ischemic liver lobes in vivo. This was associated with increased NET markers, serum level of myeloperoxidase (MPO)-DNA complexes and tissue level of citrullinated-histone H3 compared to control mice. Treatment with peptidyl-arginine-deiminase (PAD) 4 inhibitor or DNase I significantly protected hepatocytes and reduced inflammation after liver I/R as evidenced by inhibition of NET formation, indicating the pathophysiological role of NETs in liver I/R injury. In vitro, NETs increase hepatocyte death and induce Kupffer cells to release proinflammatory cytokines. DAMPs, such as HMGB1 and histones, released by injured hepatocytes stimulate NET formation through Toll-like receptor (TLR4)- and TLR9-MyD88 signaling pathways. After neutrophil depletion in mice, the adoptive transfer of TLR4 knockout (KO) or TLR9 KO neutrophils confers significant protection from liver I/R injury with significant decrease in NET formation. In addition, we found inhibition of NET formation by PAD4 inhibitor or DNase I reduces HMGB1 and histone-mediated liver I/R injury. DAMPs released during liver I/R promotes NET formation through TLRs signaling pathway. Development of NETs subsequently exacerbates organ damage and initiates inflammatory responses during liver I/R.