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TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-& kappa;B/MAPK Signaling in Transgenic Mammal Models

文献类型： 外文期刊

作者： Wang, Sutian 1 ; Zhang, Kunli 2 ; Song, Xuting 3 ; Huang, Qiuyan 1 ; Lin, Sen 4 ; Deng, Shoulong 5 ; Qi, Meiyu 7 ; Yang, Yecheng 1 ; Lu, Qi 3 ; Zhao, Duowei 3 ; Meng, Fanming 1 ; Li, Jianhao 1 ; Lian, Zhengxing 8 ; Luo, Chenglong 1 ; Yao, Yuchang 3 ;

作者机构： 1.Guangdong Acad Agr Sci, Inst Anim Sci, State Key Lab Swine & Poultry Breeding Ind, Guangdong Key Lab Anim Breeding & Nutr, Guangzhou 510640, Peoples R China

2.Guangdong Acad Agr Sci, Sci Observat & Expt Stn Vet Drugs & Diagnost Tech, Minist Agr & Rural Affairs, Inst Anim Hlth,Guangdong Prov Key Lab Livestock Di, Guangzhou 510640, Peoples R China

3.Northeast Agr Univ, Coll Anim Sci & Technol, Harbin 150030, Peoples R China

4.Guangdong Acad Agr Sci, Sericultural & Agrifood Res Inst, Guangzhou 510640, Peoples R China

5.Chinese Acad Med Sci, Inst Lab Anim Sci, Peking Union Med Coll, Beijing 100021, Peoples R China

6.Peking Union Med Coll, Comparat Med Ctr, Beijing 100021, Peoples R China

7.Heilongjiang Acad Agr Sci, Inst Anim Husb, Harbin 150028, Peoples R China

8.China Agr Univ, Coll Anim Sci & Technol, Key Lab Anim Genet & Breeding Minist Agr, Beijing Key Lab Anim Genet Improvement,Natl Engn L, Beijing 100083, Peoples R China

关键词： Toll-like receptor 4; transgenic animal model; autophagy; apoptosis; inflammation; oxidative stress

期刊名称：CELLS （ 影响因子：6.0； 五年影响因子：6.7 ）

ISSN：

年卷期： 2023 年 12 卷 13 期

页码：

收录情况： SCI

摘要： Gram-negative bacterial infections pose a significant threat to public health. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and induces innate immune responses, autophagy, and cell death, which have major impacts on the body's physiological homeostasis. However, the role of TLR4 in bacterial LPS-induced autophagy and apoptosis in large mammals, which are closer to humans than rodents in many physiological characteristics, remains unknown. So far, few reports focus on the relationship between TLR, autophagy, and apoptosis in large mammal levels, and we urgently need more tools to further explore their crosstalk. Here, we generated a TLR4-enriched mammal model (sheep) and found that a high-dose LPS treatment blocked autophagic degradation and caused strong innate immune responses and severe apoptosis in monocytes/macrophages of transgenic offspring. Excessive accumulation of autophagosomes/autolysosomes might contribute to LPS-induced apoptosis in monocytes/macrophages of transgenic animals. Further study demonstrated that inhibiting TLR4 downstream NF-& kappa;B or p38 MAPK signaling pathways reversed the LPS-induced autophagy activity and apoptosis. These results indicate that the elevated TLR4 aggravates LPS-induced monocytes/macrophages apoptosis by leading to lysosomal dysfunction and impaired autophagic flux, which is associated with TLR4 downstream NF-& kappa;B and MAPK signaling pathways. This study provides a novel TLR4-enriched mammal model to study its potential effects on autophagy activity, inflammation, oxidative stress, and cell death. These findings also enrich the biological functions of TLR4 and provide powerful evidence for bacterial infection.

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