NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice.
NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice.
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DOI：
10.1016/j.jhep.2017.01.022
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发表时间：
2017-05
影响因子：
25.7
通讯作者：
Farrell GC
中科院分区：
文献类型：
--
作者：
Mridha AR;Wree A;Robertson AAB;Yeh MM;Johnson CD;Van Rooyen DM;Haczeyni F;Teoh NC;Savard C;Ioannou GN;Masters SL;Schroder K;Cooper MA;Feldstein AE;Farrell GC
NOD样受体蛋白3（NLRP 3）炎性小体激活发生在非酒精性脂肪性肝病（NAFLD）中。我们使用第一个小分子NLRP 3抑制剂，MCC 950，来测试炎性小体阻断是否会改变两种脂肪性肝炎小鼠模型中的炎症募集和肝纤维化。我们给foz/foz和野生型小鼠喂食致动脉粥样硬化饮食16周，灌胃MCC 950或载体直到24周，然后确定NAFLD表型。在喂食蛋氨酸/胆碱缺乏（MCD）饲料的小鼠中，我们灌胃MCC 950或溶剂6周，并测定对肝纤维化的影响。在溶剂处理的foz/foz小鼠中，24周时NLRP 3、pro-IL-1β、活性caspase-1和IL-1β的肝脏表达增加，与胆固醇晶体形成和NASH病理学相关;血浆IL-1β、IL-6、MCP-1、ALT/AST均增加。MCC 950治疗使肝半胱天冬酶1和IL-1β表达、血浆IL-1β、MCP-1和IL-6正常化，降低了ALT/AST，并降低了肝脏炎症的严重程度，包括指定为NASH病理和肝纤维化。在体外，胆固醇晶体激活枯否细胞和巨噬细胞释放IL-1β; MCC 950消除了这一点，以及相关的中性粒细胞迁移。喂食MCD饲料的小鼠发生了纤维化脂肪性肝炎; MCC 950抑制了肝半胱天冬酶1和IL-1β的增加，降低了肝脏中巨噬细胞和中性粒细胞的数量，并改善了肝纤维化。NLRP 3选择性抑制剂MCC 950可改善肥胖糖尿病小鼠的NAFLD病理和纤维化。这可能是由于胆固醇晶体介导的NLRP 3在骨髓细胞中的激活被阻断。MCC 950可减少喂食MCD的小鼠的肝纤维化。以NLRP 3为靶点是NASH药物治疗的合理方向。脂肪肝是由超重、糖尿病和心脏病发作的高风险引起的，称为非酒精性脂肪性肝炎（NASH），是目前最常见的严重肝病，没有治疗方法。NASH中可能有几种炎症原因，但细胞内称为炎性体（NLRP 3）的蛋白质支架的激活已被认为起作用。在这里，我们表明胆固醇晶体可能是激活NASH炎性小体的一种途径。我们使用了一种名为MCC 950的药物，该药物已被证明可以阻断NLRP 3的激活，试图减少NASH的肝损伤。这种药物部分逆转了肝脏炎症，特别是在肥胖糖尿病小鼠中，这与NASH的人类背景最为相似。此外，用MCC 950实现的NASH中肝脏炎症的这种抑制部分逆转了肝脏瘢痕形成，该过程将NASH与肝硬化的发展联系起来。
NOD-like receptor protein 3 (NLRP3) inflammasome activation occurs in Non-alcoholic fatty liver disease (NAFLD). We used the first small molecule NLRP3 inhibitor, MCC950, to test whether inflammasome blockade alters inflammatory recruitment and liver fibrosis in two murine models of steatohepatitis. We fed foz/foz and wild-type mice an atherogenic diet for 16 weeks, gavaged MCC950 or vehicle until 24 weeks, then determined NAFLD phenotype. In mice fed an methionine/choline deficient (MCD) diet, we gavaged MCC950 or vehicle for 6 weeks and determined the effects on liver fibrosis. In vehicle-treated foz/foz mice, hepatic expression of NLRP3, pro-IL-1β, active caspase-1 and IL-1β increased at 24 weeks, in association with cholesterol crystal formation and NASH pathology; plasma IL-1β, IL-6, MCP-1, ALT/AST all increased. MCC950 treatment normalized hepatic caspase 1 and IL-1β expression, plasma IL-1β, MCP-1 and IL-6, lowered ALT/AST, and reduced the severity of liver inflammation including designation as NASH pathology, and liver fibrosis. In vitro, cholesterol crystals activated Kupffer cells and macrophages to release IL-1β; MCC950 abolished this, and the associated neutrophil migration. MCD diet-fed mice developed fibrotic steatohepatitis; MCC950 suppressed the increase in hepatic caspase 1 and IL-1β, lowered numbers of macrophages and neutrophils in the liver, and improved liver fibrosis. MCC950, an NLRP3 selective inhibitor, improved NAFLD pathology and fibrosis in obese diabetic mice. This is potentially attributable to the blockade of cholesterol crystal-mediated NLRP3 activation in myeloid cells. MCC950 reduced liver fibrosis in MCD-fed mice. Targeting NLRP3 is a logical direction in pharmacotherapy of NASH. Fatty liver disease caused by being overweight with diabetes and a high risk of heart attack, termed non-alcoholic steatohepatitis (NASH), is the most common serious liver disease with no current treatment. There could be several causes of inflammation in NASH, but activation of a protein scaffold within cells termed the inflammasome (NLRP3) has been suggested to play a role. Here we show that cholesterol crystals could be one pathway to activate the inflammasome in NASH. We used a drug called MCC950, which has already been shown to block NLRP3 activation, in an attempt to reduce liver injury in NASH. This drug partly reversed liver inflammation, particularly in obese diabetic mice that most closely resembles the human context of NASH. In addition, such dampening of liver inflammation in NASH achieved with MCC950 partly reversed liver scarring, the process that links NASH to the development of cirrhosis.
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DOI：
10.1111/j.1440-1746.2009.05996.x
发表时间：
2009-10-01
影响因子：
4.1
作者：
Larter, Claire Z.;Yeh, Matthew M.;Farrell, Geoffrey C.
通讯作者：
Farrell, Geoffrey C.
影响因子：
13.5
作者：
Csak, Timea;Ganz, Michal;Pespisa, Justin;Kodys, Karen;Dolganiuc, Angela;Szabo, Gyongyi
通讯作者：
Szabo, Gyongyi
影响因子：
3.7
作者：
Dixon LJ;Flask CA;Papouchado BG;Feldstein AE;Nagy LE
通讯作者：
Nagy LE
DOI：
10.1152/ajpgi.00301.2011
发表时间：
2012-01-01
影响因子：
4.5
作者：
Kakisaka, Keisuke;Cazanave, Sophie C.;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
15.9
作者：
Leclercq, IA;Farrell, GC;Robertson, GR
通讯作者：
Robertson, GR