Objective 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. Design 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. Results 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. Conclusion ATMs from obese vAT induce hepatic macrophage accumulation during NASH development, possibly by enhancing neutrophil recruitment.

中文翻译：

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脂肪组织巨噬细胞诱导小鼠肝脏中性粒细胞募集和巨噬细胞积累

目的 肥胖是非酒精性脂肪性肝炎 (NASH) 的危险因素。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。CD11c+ 促炎脂肪组织巨噬细胞 (ATM) 的积累是 vAT 炎症的重要驱动因素。我们研究了 ATM 在 NASH 发展过程中肝脏炎症中的作用。从瘦、肥胖或 ATM 耗尽（使用氯膦酸盐脂质体）肥胖小鼠中分离的设计 vAT 被移植到瘦 ldlr-/- 受体小鼠。在标准食物 2 周后或高胆固醇饮食 (HCD) 8 周后评估全身和肝脏炎症以诱导 NASH。结果 与瘦肉移植小鼠相比，移植肥胖小鼠的供体 vAT 增加了 HCD 诱导的肝巨噬细胞含量，加重了肝损伤。vAT 移植前 ATM 消耗减少了这种增加的肝巨噬细胞积累。在食物中，vAT 移植诱导肥胖移植小鼠的循环和肝脏中性粒细胞数量比瘦移植小鼠更显着增加，而 vAT 移植前的 ATM 耗竭逆转了这种效果。从供体脂肪组织中分离的 CD11c+ 和 CD11c- 巨噬细胞的荧光激活细胞分选的微阵列分析表明，肥胖导致中性粒细胞趋化基因的表达增强，特别是在 CD11c+ ATM 中。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，CD11c 在肥胖个体 vAT 中的表达与中性粒细胞趋化基因的 vAT 表达以及中性粒细胞和巨噬细胞标记基因的肝脏表达相关。结论 来自肥胖 vAT 的 ATM 在 NASH 发展过程中诱导肝脏巨噬细胞积累，可能是通过增强中性粒细胞募集。