Pierce Andrew A, Duwaerts Caroline C, Siao Kevin, Mattis Aras N, Goodsell Amanda, Baron Jody L, Maher Jacquelyn J
Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America.
Liver Center, University of California, San Francisco, San Francisco, California, United States of America.
PLoS One. 2017 Sep 5;12(9):e0183912. doi: 10.1371/journal.pone.0183912. eCollection 2017.
Neutrophils and macrophages are important constituents of the hepatic inflammatory infiltrate in non-alcoholic steatohepatitis. These innate immune cells express CD18, an adhesion molecule that facilitates leukocyte activation. In the context of fatty liver, activation of infiltrated leukocytes is believed to enhance hepatocellular injury. The objective of this study was to determine the degree to which activated innate immune cells promote steatohepatitis by comparing hepatic outcomes in wild-type and CD18-mutant mice fed a methionine-choline-deficient (MCD) diet. After 3 weeks of MCD feeding, hepatocyte injury, based on serum ALT elevation, was 40% lower in CD18-mutant than wild-type mice. Leukocyte infiltration into the liver was not impaired in CD18-mutant mice, but leukocyte activation was markedly reduced, as shown by the lack of evidence of oxidant production. Despite having reduced hepatocellular injury, CD18-mutant mice developed significantly more hepatic steatosis than wild-type mice after MCD feeding. This coincided with greater hepatic induction of pro-inflammatory and lipogenic genes as well as a modest reduction in hepatic expression of adipose triglyceride lipase. Overall, the data indicate that CD18 deficiency curbs MCD-mediated liver injury by limiting the activation of innate immune cells in the liver without compromising intrahepatic cytokine activation. Reduced liver injury occurs at the expense of increased hepatic steatosis, which suggests that in addition to damaging hepatocytes, infiltrating leukocytes may influence lipid homeostasis in the liver.
中性粒细胞和巨噬细胞是非酒精性脂肪性肝炎中肝脏炎性浸润的重要组成部分。这些固有免疫细胞表达CD18，这是一种促进白细胞活化的黏附分子。在脂肪肝的情况下，浸润的白细胞活化被认为会加重肝细胞损伤。本研究的目的是通过比较喂食蛋氨酸-胆碱缺乏（MCD）饮食的野生型和CD18突变型小鼠的肝脏结局，来确定活化的固有免疫细胞促进脂肪性肝炎的程度。在喂食MCD 3周后，基于血清ALT升高的肝细胞损伤在CD18突变型小鼠中比野生型小鼠低40%。CD18突变型小鼠肝脏中的白细胞浸润未受损，但白细胞活化明显减少，这表现为缺乏氧化剂产生的证据。尽管肝细胞损伤减轻，但CD18突变型小鼠在喂食MCD后发生的肝脏脂肪变性明显比野生型小鼠更多。这与肝脏中促炎和脂肪生成基因的诱导增加以及肝脏中脂肪甘油三酯脂肪酶表达的适度降低相一致。总体而言，数据表明CD18缺陷通过限制肝脏中固有免疫细胞的活化来抑制MCD介导的肝损伤，而不影响肝内细胞因子的活化。肝损伤减轻是以肝脏脂肪变性增加为代价的，这表明除了损害肝细胞外，浸润的白细胞可能会影响肝脏中的脂质稳态。
