Petrasek Jan, Iracheta-Vellve Arvin, Saha Banishree, Satishchandran Abhishek, Kodys Karen, Fitzgerald Katherine A, Kurt-Jones Evelyn A, Szabo Gyongyi
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
J Leukoc Biol. 2015 Aug;98(2):249-56. doi: 10.1189/jlb.3AB1214-590R. Epub 2015 May 1.
Inflammation defines the progression of ALD from reversible to advanced stages. Translocation of bacterial LPS to the liver from the gut is necessary for alcohol-induced liver inflammation. However, it is not known whether endogenous, metabolic danger signals are required for inflammation in ALD. Uric acid and ATP, 2 major proinflammatory danger signals, were evaluated in the serum of human volunteers exposed to a single dose of ethanol or in supernatants of primary human hepatocytes exposed to ethanol. In vitro studies were used to evaluate the role of uric acid and ATP in inflammatory cross-talk between hepatocytes and immune cells. The significance of signaling downstream of uric acid and ATP in the liver was evaluated in NLRP3-deficient mice fed a Lieber-DeCarli ethanol diet. Exposure of healthy human volunteers to a single dose of ethanol resulted in increased serum levels of uric acid and ATP. In vitro, we identified hepatocytes as a significant source of these endogenous inflammatory signals. Uric acid and ATP mediated a paracrine inflammatory cross-talk between damaged hepatocytes and immune cells and significantly increased the expression of LPS-inducible cytokines, IL-1β and TNF-α, by immune cells. Deficiency of NLRP3, a ligand-sensing component of the inflammasome recognizing uric acid and ATP, prevented the development of alcohol-induced liver inflammation in mice and significantly ameliorated liver damage and steatosis. Endogenous metabolic danger signals, uric acid, and ATP are involved in inflammatory cross-talk between hepatocytes and immune cells and play a crucial role in alcohol-induced liver inflammation.
炎症决定了酒精性肝病（ALD）从可逆阶段发展到晚期阶段的进程。肠道细菌脂多糖（LPS）向肝脏的移位是酒精诱导肝脏炎症所必需的。然而，目前尚不清楚内源性代谢危险信号是否是ALD炎症所必需的。对接受单剂量乙醇的人类志愿者血清或接受乙醇处理的原代人肝细胞上清液中的两种主要促炎危险信号尿酸和三磷酸腺苷（ATP）进行了评估。体外研究用于评估尿酸和ATP在肝细胞与免疫细胞之间炎症相互作用中的作用。在喂食Lieber-DeCarli乙醇饮食的NLRP3缺陷小鼠中评估了肝脏中尿酸和ATP下游信号传导的意义。健康人类志愿者接受单剂量乙醇后，血清尿酸和ATP水平升高。在体外，我们确定肝细胞是这些内源性炎症信号的重要来源。尿酸和ATP介导了受损肝细胞与免疫细胞之间的旁分泌炎症相互作用，并显著增加了免疫细胞中LPS诱导的细胞因子白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的表达。NLRP3是炎性小体的一种配体感应成分，可识别尿酸和ATP，其缺陷可预防小鼠酒精性肝炎症的发展，并显著改善肝损伤和脂肪变性。内源性代谢危险信号尿酸和ATP参与肝细胞与免疫细胞之间的炎症相互作用，并在酒精性肝炎症中起关键作用。
