Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China.
Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China.
Acta Biochim Biophys Sin (Shanghai). 2021 Apr 15;53(5):601-611. doi: 10.1093/abbs/gmab030.
Liver ischemia/reperfusion injury (IRI), a serious inflammatory response driven by innate immunity, occurs in liver surgeries such as liver resection and liver transplantation, leading to liver dysfunction, liver failure, and even rejection after transplantation. Liver kinase B1 (LKB1) plays a pivotal anti-inflammatory role in IRI. One of the most important factors involved in liver IRI is the aberrant activation of the nucleotide binding oligomerization domain like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome in Kupffer cells. However, the mechanisms underlying the effect of LKB1 on the NLRP3 inflammasome in liver IRI remain elusive. In this study, we found that the expression of LKB1 was decreased in liver IRI, while the NLRP3 inflammasome level was increased as shown, as revealed by RT-qPCR and western blot analysis. Furthermore, upregulation of LKB1 abrogated the expression of the NLRP3 inflammasome, which improved liver function and liver pathology in the liver IRI model in vivo. In vitro, overexpression of LKB1 inhibited the activation of NLRP3 inflammasome and nuclear factor-κB, while the inhibitory effect was reversed by silencing the expression of the forkhead box protein O1 in the RAW264.7 macrophage hypoxia/reoxygenation model. In conclusion, our results suggest that LKB1 exerts a protective effect against liver IRI by downregulating the NLRP3 inflammasome.
肝缺血/再灌注损伤（IRI）是一种由固有免疫驱动的严重炎症反应，发生在肝切除术和肝移植等肝手术中，导致肝功能障碍、肝衰竭，甚至移植后排斥。肝激酶 B1（LKB1）在 IRI 中发挥着关键的抗炎作用。肝 IRI 中涉及的最重要因素之一是库普弗细胞中核苷酸结合寡聚结构域样受体（NLR）家族、pyrin 结构域包含 3（NLRP3）炎性小体的异常激活。然而，LKB1 对肝 IRI 中 NLRP3 炎性小体的作用机制仍不清楚。在这项研究中，我们发现 LKB1 的表达在肝 IRI 中降低，而 NLRP3 炎性小体的水平如 RT-qPCR 和 western blot 分析所示增加。此外，上调 LKB1 可消除 NLRP3 炎性小体的表达，从而改善体内肝 IRI 模型中的肝功能和肝病理。在体外，LKB1 的过表达抑制 NLRP3 炎性小体和核因子-κB 的激活，而沉默 RAW264.7 巨噬细胞缺氧/复氧模型中叉头框蛋白 O1 的表达则逆转了这种抑制作用。总之，我们的结果表明，LKB1 通过下调 NLRP3 炎性小体对肝 IRI 发挥保护作用。
