Department of Internal Medicine, MUMC, Maastricht, Limburg, The Netherlands.
Cardiovascular Research Institute Maastricht, MUMC, Maastricht, Limburg, The Netherlands.
Gut. 2018 Jul;67(7):1317-1327. doi: 10.1136/gutjnl-2016-313654. Epub 2017 Oct 26.
Obesity is a risk factor for non-alcoholic steatohepatitis (NASH). This risk has been attributed to visceral adipose tissue (vAT) expansion associated with increased proinflammatory mediators. Accumulation of CD11c proinflammatory adipose tissue macrophages (ATM) is an important driver of vAT inflammation. We investigated the role of ATMs in hepatic inflammation during NASH development.
vAT isolated from lean, obese or ATM-depleted (using clodronate liposomes) obese mice was transplanted to lean ldlr acceptor mice. Systemic and hepatic inflammation was assessed either after 2 weeks on standard chow or after 8 weeks on high cholesterol diet (HCD) to induce NASH.
Transplanting donor vAT from obese mice increased HCD-induced hepatic macrophage content compared with lean-transplanted mice, worsening liver damage. ATM depletion prior to vAT transplantation reduced this increased hepatic macrophage accumulation. On chow, vAT transplantation induced a more pronounced increase in circulating and hepatic neutrophil numbers in obese-transplanted than lean-transplanted mice, while ATM depletion prior to vAT transplantation reversed this effect. Microarray analysis of fluorescence-activated cell sorting of CD11c and CD11c macrophages isolated from donor adipose tissue showed that obesity resulted in enhanced expression of neutrophil chemotaxis genes specifically in CD11c ATMs. Involvement of the neutrophil chemotaxis proteins, CXCL14 and CXCL16, was confirmed by culturing vAT. In humans, CD11c expression in vAT of obese individuals correlated with vAT expression of neutrophil chemotactic genes and with hepatic expression of neutrophil and macrophage marker genes.
ATMs from obese vAT induce hepatic macrophage accumulation during NASH development, possibly by enhancing neutrophil recruitment.
肥胖是非酒精性脂肪性肝炎（NASH）的一个危险因素。这种风险归因于与促炎介质增加相关的内脏脂肪组织（vAT）扩张。积累促炎的 CD11c 脂肪组织巨噬细胞（ATM）是 vAT 炎症的一个重要驱动因素。我们研究了在 NASH 发展过程中 ATM 在肝炎症中的作用。
从瘦鼠、肥胖鼠或 ATM 耗竭（使用氯膦酸盐脂质体）肥胖鼠分离的 vAT 被移植到瘦 ldlr 接受鼠。在标准饲料上 2 周后或在高胆固醇饮食（HCD）上 8 周后评估系统和肝炎症，以诱导 NASH。
与瘦鼠移植相比，从肥胖鼠移植的供体 vAT 增加了 HCD 诱导的肝巨噬细胞含量，导致肝损伤加重。在 vAT 移植前耗竭 ATM 减少了这种肝巨噬细胞积累的增加。在正常饮食中，与瘦鼠移植相比，肥胖鼠移植增加了循环和肝中性粒细胞数量，而在 vAT 移植前耗竭 ATM 则逆转了这种效应。对从供体脂肪组织分离的 CD11c 和 CD11c 巨噬细胞进行荧光激活细胞分选的微阵列分析表明，肥胖导致 CD11c ATM 中特定的中性粒细胞趋化基因表达增强。通过培养 vAT 证实了中性粒细胞趋化蛋白 CXCL14 和 CXCL16 的参与。在人类中，肥胖个体 vAT 中的 CD11c 表达与 vAT 中中性粒细胞趋化基因的表达以及肝中性粒细胞和巨噬细胞标记基因的表达相关。
肥胖 vAT 的 ATM 在 NASH 发展过程中诱导肝巨噬细胞积累，可能通过增强中性粒细胞募集来实现。
