Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
Hepatology. 2018 Oct;68(4):1604-1620. doi: 10.1002/hep.29919. Epub 2018 May 10.
Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), a key antibacterial protein, is highly elevated in patients with end-stage liver disease that is often associated with bacterial infection. LCN2 is expressed at high levels in both hepatocytes and neutrophils; however, how hepatocyte-derived and neutrophil-derived LCN2 cooperate to combat bacterial infection remains unclear. Here, by studying hepatocyte-specific and myeloid-specific Lcn2 knockout mice in two models of systemic and local Klebsiella pneumoniae infections, we demonstrated that hepatocytes played a critical role in controlling systemic infection by secreting LCN2 protein into the circulation following intraperitoneal injection of bacteria, whereas neutrophils were more important in combating local lung infection by carrying LCN2 in their specific granules to the local infection site following intratracheal intubation of bacteria. Both hepatocyte-derived and myeloid cell-derived LCN2 were required against bacterial infection in the peritoneal cavity and liver necrotic areas following intraperitoneal injection of Klebsiella pneumoniae. LCN2/NGAL protein was detected in neutrophil extracellular traps (NETs) in activated neutrophils from mice and humans. Disruption of the Lcn2 gene in neutrophils abolished LCN2 on NETs, whereas deletion of this gene in hepatocytes did not affect LCN2 protein on NETs. Genetic deletion of the Lcn2 gene globally or specifically in neutrophils did not affect NET formation but reduced the bactericidal effect of NETs in vitro. Finally, NGAL-positive NETs were detected in the liver from patients with various types of liver diseases.
Both hepatocytes and neutrophils combat bacterial infection through the production of LCN2; extracellular LCN2 secreted by hepatocytes limits systemic bacterial infection, whereas neutrophils carry LCN2 protein to the local site and against local bacterial infection through NETs. (Hepatology 2018).
脂联素-2（LCN2），也称为中性粒细胞明胶酶相关脂质运载蛋白（NGAL），是一种关键的抗菌蛋白，在终末期肝病患者中高度升高，终末期肝病常伴有细菌感染。LCN2 在肝细胞和中性粒细胞中均高表达；然而，肝细胞源性和中性粒细胞源性 LCN2 如何合作来对抗细菌感染尚不清楚。在这里，通过研究两种全身和局部肺炎克雷伯菌感染模型中的肝细胞特异性和髓样细胞特异性 Lcn2 敲除小鼠，我们证明肝细胞在通过腹腔内注射细菌将 LCN2 蛋白分泌到循环中后在控制全身感染方面起着关键作用，而中性粒细胞通过将 LCN2 携带在其特异性颗粒中到局部感染部位在经气管内插管细菌后在对抗局部肺部感染方面更为重要。在经腹腔内注射肺炎克雷伯菌后，无论是在腹腔还是在肝坏死区域，肝细胞源性和髓样细胞源性 LCN2 都需要抵抗细菌感染。在从小鼠和人类激活的中性粒细胞中检测到中性粒细胞细胞外陷阱（NETs）中的 LCN2/NGAL 蛋白。在中性粒细胞中破坏 Lcn2 基因会使 NETs 上的 LCN2 失活，而在肝细胞中删除该基因则不会影响 NETs 上的 LCN2 蛋白。在中性粒细胞中全局或特异性地删除 Lcn2 基因不会影响 NET 的形成，但会降低 NETs 在体外的杀菌作用。最后，在患有各种类型肝病的患者的肝脏中检测到 NGAL 阳性 NETs。
肝细胞和中性粒细胞通过产生 LCN2 来对抗细菌感染；肝细胞分泌的细胞外 LCN2 限制全身细菌感染，而中性粒细胞通过 NET 将 LCN2 蛋白携带到局部部位并对抗局部细菌感染。（Hepatology 2018）。
