TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models
Sutian Wang,
Kunli Zhang,
Xuting Song,
Qiuyan Huang,
Sen Lin,
Shoulong Deng,
Meiyu Qi,
Yecheng Yang,
Qi Lu,
Duowei Zhao,
Fanming Meng,
Jianhao Li,
Zhengxing Lian,
Chenglong Luo,
Yuchang Yao
Affiliations
Sutian Wang
State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
Kunli Zhang
Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangdong Provincial Key Laboratory of Livestock Disease Prevention Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Guangzhou 510640, China
Xuting Song
College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
Qiuyan Huang
State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
Sen Lin
Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
Shoulong Deng
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China
Meiyu Qi
Institute of Animal Husbandry, Heilongjiang Academy of Agricultural Sciences, Harbin 150028, China
Yecheng Yang
State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
Qi Lu
College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
Duowei Zhao
College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
Fanming Meng
State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
Jianhao Li
State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
Zhengxing Lian
Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100083, China
Chenglong Luo
State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
Yuchang Yao
College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
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-κB 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-κB 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.
