Busulfan and cyclosphamide induce liver inflammation through NLRP3 activation in mice after hematopoietic stem cell transplantation.
Busulfan and cyclosphamide induce liver inflammation through NLRP3 activation in mice after hematopoietic stem cell transplantation.
复制标题
白消安和环磷酰胺通过造血干细胞移植后小鼠的 NLRP3 激活诱导肝脏炎症。
DOI：
10.1038/srep17828
复制
发表时间：
2015-12-04
影响因子：
4.6
通讯作者：
Zeng L
中科院分区：
文献类型：
--
作者：
Qiao J;Huang Y;Xia Y;Chu P;Yao H;Xu L;Qi K;Liu Y;Xu K;Zeng L
本研究的目的是评估NLRP 3炎性体在BU/CY诱导的小鼠HSCT后肝脏炎症中的作用。采用BU/CY预处理后的5 × 106骨髓单个核细胞输注建立HSCT小鼠模型。HSCT后第7、14、21和28天处死小鼠，分析肝脏炎症、细胞因子分泌、NLRP 3表达和caspase-1活化以及ATP和高迁移率族蛋白B1（HMGB 1）的释放。此外，NLRP 3选择性抑制剂（BAY 11-7082）被给予HSCT后的小鼠，以评估其对肝脏炎症的影响。HSCT后小鼠肝脏出现严重的炎症和损伤，IL-1β和IL-18分泌增加。同时，肝脏NLRP 3表达增加，caspase-1活性增强，ATP和HMGB 1释放增加。选择性抑制NLRP 3可降低caspase-1的活化以及IL-1β和IL-18的分泌。此外，NLRP 3抑制还减少了巨噬细胞和嗜中性粒细胞的浸润，并改善了肝功能。结论：NLRP 3参与了BU/CY诱导的HSCT后肝脏炎症反应，并选择性抑制其表达，改善肝脏炎症反应，改善肝功能，提示靶向NLRP 3可能成为预防HSCT后肝脏炎症反应的新途径。
The aim of this study was to evaluate the role of NLRP3 inflammasome on BU/CY-induced liver inflammation in mice after HSCT. HSCT mice model was established through infusion of 5 × 106bone marrow mononuclear cells after conditioned with BU/CY. On day 7, 14, 21 and 28 after HSCT, mice were sacrificed for analysis of liver inflammation, cytokine secretion, NLRP3 expression and caspase-1 activation as well as release of ATP and high-mobility group protein B1 (HMGB1). Furthermore, NLRP3 selective inhibitor (BAY 11-7082) was administrated into mice after HSCT to evaluate its effects on liver inflammation. Severe liver inflammation and damage with elevated secretion of IL-1β and IL-18 were found in mice after HSCT. Meanwhile, elevated expressions of NLRP3 and caspase-1 activation in liver were found. In addition, increased release of ATP and HMGB1 were observed. Selective inhibition of NLRP3 decreased caspase-1 activation and secretion of IL-1β and IL-18. Furthermore, NLRP3 inhibition also reduced infiltration of macrophages and neutrophils and improved liver function. In conclusion, NLRP3 was involved in BU/CY-induced liver inflammation after HSCT and selectively inhibited it ameliorated liver inflammation and improved liver function, suggesting targeting NLRP3 might be a new approach in the prophylaxis of liver inflammation after HSCT.