Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice.
Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice.
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DOI：
10.1002/hep.26081
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发表时间：
2013-02
期刊：
影响因子：
13.5
通讯作者：
Seki, Ekihiro
中科院分区：
文献类型：
--
作者：
Miura, Kouichi;Yang, Ling;van Rooijen, Nico;Brenner, David A.;Ohnishi, Hirohide;Seki, Ekihiro
与Toll样受体（TLRs）相关的先天免疫信号是参与非酒精性脂肪性肝炎（NASH）进展的关键途径。在这里，我们发现TLR2和棕榈酸都是激活炎性体、IL-1α和IL-1β所必需的，从而导致NASH的进展。野生型（WT）和TLR2 - / -小鼠喂食胆碱缺乏氨基酸（CDAA）饲料22周以诱导NASH。受体小鼠经致死性照射后，产生骨髓移植- tlr2嵌合小鼠。从WT小鼠中分离Kupffer细胞和肝星状细胞（hsc），用TLR2配体和/或棕榈酸刺激。CDAA饮食的WT小鼠发生重度脂肪性肝炎和肝纤维化。相比之下，TLR2 - / -小鼠抑制了NASH的进展。虽然Kupffer细胞和hsc都对TLR2配体有反应，但TLR2骨髓嵌合小鼠表明，在TLR2介导的NASH进展中，Kupffer细胞比hsc相对更重要。在体外，单独使用棕榈酸不会增加库普弗细胞和造血干细胞中TLR2信号靶基因，包括细胞因子和炎性体成分。TLR2配体在库普弗细胞中增加nod样受体蛋白3（一种炎性体成分），但在造血干细胞中没有增加。在TLR2配体存在的情况下，棕榈酸确实诱导了Kupffer细胞中caspase-1的激活和IL-1α和IL-1β的释放，但在hsc中没有观察到这些作用。在体内，WT在CDAA饮食中显示肝脏caspase-1激活增加，血清IL-1α和IL-1β水平升高，而在TLR2−/−小鼠中被抑制。结论：TLR2和棕榈酸共同激活库普弗细胞/巨噬细胞中的炎性体，参与NASH的发生。
Innate immune signaling associated with Toll like receptors (TLRs) is a key pathway involved in the progression of nonalcoholic steatohepatitis (NASH). Here we show that both TLR2 and palmitic acid are required for activation of the inflammasome, IL-1α and IL-1β, resulting in the progression of NASH. Wild type (WT) and TLR2−/− mice were fed a choline deficient amino acid defined (CDAA) diet for 22 weeks to induce NASH. Bone marrow transplanted-TLR2 chimeric mice were generated after the recipient mice were lethally irradiated. Kupffer cells and hepatic stellate cells (HSCs) were isolated from WT mice and stimulated with TLR2 ligand and/or palmitic acid. WT mice on the CDAA diet developed profound steatohepatitis and liver fibrosis. In contrast, TLR2−/− mice had suppressed progression of NASH. While both Kupffer cells and HSCs respond to TLR2 ligand, TLR2 bone marrow chimeric mice demonstrated that Kupffer cells were relatively more important than HSCs in TLR2-mediated progression of NASH. In vitro, palmitic acid alone did not increase TLR2 signaling-target genes including cytokines and inflammasome components in Kupffer cells and HSCs. The TLR2 ligand increased Nod-like receptor protein 3, an inflammasome component, in Kupffer cells, but not in HSCs. In the presence of TLR2 ligand, palmitic acid did induce caspase-1 activation and release of IL-1α and IL-1β in Kupffer cells, however, these effects were not observed in HSCs. In vivo, WT on the CDAA diet showed increased caspase-1 activation in the liver and elevated serum levels of IL-1α and IL-1β levels, which were suppressed in TLR2−/− mice. Conclusion: TLR2 and palmitic acid cooperatively activate inflammasome in Kupffer cells/macrophages in the development of NASH.
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影响因子：
29.4
作者：
Miura K;Kodama Y;Inokuchi S;Schnabl B;Aoyama T;Ohnishi H;Olefsky JM;Brenner DA;Seki E
通讯作者：
Seki E
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
DOI：
10.1111/j.1530-0277.2011.01487.x
发表时间：
2011-08
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Inokuchi S;Tsukamoto H;Park E;Liu ZX;Brenner DA;Seki E
通讯作者：
Seki E
影响因子：
8.2
作者：
Ehses, J. A.;Meier, D. T.;Donath, Marc Y.
通讯作者：
Donath, Marc Y.
DOI：
10.4049/jimmunol.0901363
发表时间：
2009-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bauernfeind FG;Horvath G;Stutz A;Alnemri ES;MacDonald K;Speert D;Fernandes-Alnemri T;Wu J;Monks BG;Fitzgerald KA;Hornung V;Latz E
通讯作者：
Latz E