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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice
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Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice

机译：Toll样受体2和棕榈酸通过激活小鼠的炎症小体共同促进非酒精性脂肪性肝炎的发展

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摘要

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, interleukin (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. Although 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 mice 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 the inflammasome in Kupffer cells and/or macrophages in the development of NASH.
机译：与Toll样受体（TLR）相关的先天性免疫信号传导是非酒精性脂肪性肝炎（NASH）进程中的关键途径。在这里，我们显示TLR2和棕榈酸都需要激活炎性小体，白介素（IL）-1α和IL-1β，从而导致NASH的进展。给野生型（WT）和TLR2-/-小鼠喂食胆碱缺乏氨基酸定义（CDAA）饮食22周，以诱导NASH。接受致死性辐照的小鼠后，产生了骨髓移植的TLR2嵌合小鼠。从野生型小鼠中分离出枯否细胞和肝星状细胞（HSC），并用TLR2配体和/或棕榈酸刺激。用CDAA饮食的野生型小鼠发展为严重的脂肪性肝炎和肝纤维化。相反，TLR2-/-小鼠抑制了NASH的进展。尽管库普弗细胞和HSC都对TLR2配体作出反应，但TLR2骨髓嵌合小鼠证明，库普弗细胞在TLR2介导的NASH进展中比HSC相对重要。在体外，仅棕榈酸不会增加TLR2信号传导靶基因，包括库普弗细胞和HSC中的细胞因子和炎性体成分。 TLR2配体在Kupffer细胞中增加了Nod样受体蛋白3（一种炎性体成分），但在HSC中却没有。在存在TLR2配体的情况下，棕榈酸确实能诱导库普弗细胞中caspase-1的活化以及IL-1α和IL-1β的释放。然而，在HSC中未观察到这些作用。在体内，以CDAA饮食喂养的野生型小鼠肝脏中caspase-1的激活增加，血清IL-1α和IL-1β的水平升高，而在TLR2-/-小鼠中则受到抑制。结论：TLR2和棕榈酸在NASH发生过程中协同激活Kupffer细胞和/或巨噬细胞中的炎症小体。

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