Anti-toll-like receptor 2 antibody ameliorates hepatic injury, inflammation, fibrosis and steatosis in obesity-related metabolic disorder rats via regulating MAPK and NF-kappa B pathways
Anti-toll-like receptor 2 antibody ameliorates hepatic injury, inflammation, fibrosis and steatosis in obesity-related metabolic disorder rats via regulating MAPK and NF-kappa B pathways
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抗 Toll 样受体 2 抗体通过调节 MAPK 和 NF-κ B 通路改善肥胖相关代谢性疾病大鼠的肝损伤、炎症、纤维化和脂肪变性
DOI：
10.1016/j.intimp.2020.106368
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发表时间：
2020
影响因子：
5.6
通讯作者：
Lu Shemin
中科院分区：
文献类型：
--
作者：
Wu Litao;Sun Juan;Liu Li;Du Xiaojuan;Liu Yan;Yan Xiaofei;Osoro Ezra Kombo;Zhang Fujun;Feng Lina;Liang Dong;Li Yazhao;Chen Qian;Sun Sha;Zhang Lei;Lan Xi;Li Dongmin;Lu Shemin
非酒精性脂肪性肝病（NAFLD）是世界范围内最常见的肝脏疾病之一，其包括一系列肝脏组织学变化。非酒精性脂肪性肝炎（NASH）被认为是NAFLD的进行性亚型，其特征在于基于脂肪变性的小叶炎症和细胞气球样变。迫切需要开发用于NAFLD/NASH的新颖且有效的治疗方法。Toll样受体2（TLR 2）信号通路的激活在高脂相关炎症中起关键作用，触发NASH的发生和发展。本文制备了抗TLR 2单克隆抗体（TLR 2 mAb），并在体内和体外研究了其改善炎症反应的能力。体外实验观察TLR 2单克隆抗体对NR 8383巨噬细胞和THP-1源性巨噬细胞的抗炎作用。为了进行体内验证，将3组SD大鼠分别给予20周的治疗：对照组给予标准饲料，IgG和TLR 2 mAb组分别给予高脂饲料和IgG或TLR 2 mAb。收集肝组织和血清用于进一步分析。结果显示，TLR 2 mAb治疗4周后，大鼠的代谢参数（体重、空腹血糖水平、肝脏脂肪变性、炎症反应和纤维化）明显改善。Western blotting结果显示，TLR 2 mAb可阻断MAPK和NF-κB的活化，抑制大鼠肝组织炎症因子的表达。提示TLR 2 mAb可通过抑制炎症反应、调节肝脏MAPK和NF-κB信号通路，改善HFD诱导的肝损伤、炎症、纤维化和脂肪变性。这表明TLR 2可能是代谢性疾病特别是NASH的新的治疗靶点。
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide, which includes a spectrum of histological liver changes. Non-alcoholic steatohepatitis (NASH) is considered to be the progressive subtype of NAFLD, which is characterized by lobular inflammation and cellular ballooning on the basis of steatosis. There is a critical need to develop novel and effective therapeutic approaches for NAFLD/NASH. The activation of toll-like receptor 2 (TLR2) signaling pathway plays a key role in high-fat-related inflammation, triggering the occurrence and development of NASH. Herein, the anti-TLR2 monoclonal antibody (TLR2 mAb) was prepared and investigated for its ability to ameliorate the inflammatory responsein vivoandin vitro. The anti-inflammatory role of TLR2 mAbin vitrowas examined in NR8383 macrophage cells and THP-1 derived macrophage cells. For confirmationin vivo, three groups of SD rats were treated for 20 weeks: rats in the control were fed with a standard diet; rates in the IgG and TLR2 mAb groups were fed with a high-fat diet and with IgG or TLR2 mAb, respectively. Liver tissue and serum were collected for further analysis. Results showed that after 4-week treatment with TLR2 mAb, metabolic parameters in rats were improved markedly (body weight, fasting blood glucose level, liver steatosis, inflammatory response and fibrosis). Moreover, western blotting demonstrated that the TLR2 mAb blocked MAPKs and NF-κB activation, and inhibited the expression of inflammatory factors in rat liver tissue. These effects suggested that TLR2 mAb could improve HFD-induced hepatic injury, inflammation, fibrosis and steatosis by suppressing inflammatory response and regulating the hepatic MAPKs and NF-κB signaling pathways. This suggests that TLR2 may be a novel therapeutic target for metabolic diseases especially NASH.