Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice.
Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice.
复制标题
DOI：
10.1053/j.gastro.2010.03.052
复制
发表时间：
2010-07
期刊：
影响因子：
29.4
通讯作者：
Seki E
中科院分区：
文献类型：
--
作者：
Miura K;Kodama Y;Inokuchi S;Schnabl B;Aoyama T;Ohnishi H;Olefsky JM;Brenner DA;Seki E
非酒精性脂肪性肝炎（NASH）的发展涉及先天免疫系统，并由枯否细胞和肝星状细胞（HSCs）介导。Toll样受体9（TLR9）是一种模式识别受体，它能识别细菌来源的含胞嘧啶 - 磷酸 - 鸟嘌呤（CpG）的DNA并激活先天免疫。我们研究了TLR9信号传导以及炎症细胞因子白细胞介素 - 1β（IL - 1β）在脂肪性肝炎、纤维化和胰岛素抵抗中的作用。
野生型（WT）、TLR9 - / - 、IL - 1受体（IL - 1R） - / - 和MyD88 - / - 小鼠被喂食胆碱缺乏的氨基酸限定（CDAA）饮食22周，然后对脂肪性肝炎、纤维化和胰岛素抵抗进行评估。对分离的肝细胞评估脂质积累和细胞死亡情况。分离枯否细胞和肝星状细胞以分别评估炎症和纤维化反应。
CDAA饮食在野生型小鼠中诱发了NASH，其特征为脂肪变性、炎症、纤维化和胰岛素抵抗。与野生型小鼠相比，TLR9 - / - 小鼠表现出较轻的脂肪性肝炎和肝纤维化。在炎症细胞因子中，TLR9 - / - 小鼠中IL - 1β的产生受到抑制。枯否细胞在对CpG寡脱氧核苷酸反应时产生IL - 1β。IL - 1β而非CpG - 寡脱氧核苷酸增加了肝细胞中的脂质积累。肝细胞中的脂质积累导致核因子 - κB失活，从而在对IL - 1β反应时引起细胞死亡。IL - 1β诱导肝星状细胞的纤维化反应，包括金属蛋白酶组织抑制剂 - 1的分泌。与野生型小鼠相比，IL - 1R - / - 小鼠的脂肪性肝炎和纤维化减轻。MyD88是TLR9和IL - 1R信号传导的衔接分子，MyD88缺陷小鼠的脂肪性肝炎和纤维化也减轻。在CDAA饮食下，TLR9 - / - 、IL - 1R - / - 和MyD88 - / - 小鼠比野生型小鼠的胰岛素抵抗更轻。
在NASH小鼠模型中，TLR9信号传导诱导枯否细胞产生IL - 1β，从而导致脂肪变性、炎症和纤维化。
Development of nonalcoholic steatohepatitis (NASH) involves the innate immune system and is mediated by Kupffer cells and hepatic stellate cells (HSCs). Toll-like receptor 9 (TLR9) is a pattern recognition receptor that recognizes bacteria-derived cytosine phosphate guanine (CpG)–containing DNA and activates innate immunity. We investigated the role of TLR9 signaling and the inflammatory cytokine interleukin-1β (IL-1β) in steatohepatitis, fibrosis, and insulin resistance. Wild-type (WT), TLR9−/−, IL-1 receptor (IL-1R)−/−, and MyD88−/− mice were fed a choline-deficient amino acid-defined (CDAA) diet for 22 weeks and then assessed for steatohepatitis, fibrosis, and insulin resistance. Lipid accumulation and cell death were assessed in isolated hepatocytes. Kupffer cells and HSCs were isolated to assess inflammatory and fibrogenic responses, respectively. The CDAA diet induced NASH in WT mice, characterized by steatosis, inflammation, fibrosis, and insulin resistance. TLR9−/− mice showed less steatohepatitis and liver fibrosis than WT mice. Among inflammatory cytokines, IL-1β production was suppressed in TLR9−/− mice. Kupffer cells produced IL-1β in response to CpG oligodeoxynucleotide. IL-1β but not CpG-oligodeoxynucleotides, increased lipid accumulation in hepatocytes. Lipid accumulation in hepatocytes led to nuclear factor-κB inactivation, resulting in cell death in response to IL-1β. IL-1β induced fibrogenic responses in HSCs, including secretion of tissue inhibitor of metalloproteinase-1. IL-1R−/− mice had reduced steatohepatitis and fibrosis, compared with WT mice. Mice deficient in MyD88, an adaptor molecule for TLR9 and IL-1R signaling, also had reduced steatohepatitis and fibrosis. TLR9−/−, IL-1R−/−, and MyD88−/− mice had less insulin resistance than WT mice on the CDAA diet. In a mouse model of NASH, TLR9 signaling induces production of IL-1β by Kupffer cells, leading to steatosis, inflammation, and fibrosis.